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Frontiers in Public Health 01 frontiersin.org
COVID-19 vaccination:
challenges in the pediatric
population
AliceNicoletaAzoicai
1†, IngrithMiron
1†, AncutaLupu
1*†,
MonicaMihaelaAlexoae
1†, IulianaMagdalenaStarcea
1†,
MirabelaAlecsa
1†, VasileValeriuLupu
1*†, CiprianDanielescu
2†,
AlinHoratiuNedelcu
2†, DeliaLidiaSalaru
2†, FeliciaDragan
3† and
IleanaIoniuc
1†
1 Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania, 2 Faculty of
Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania, 3 Faculty of Medicine
and Pharmacy, University of Oradea, Oradea, Romania
Vaccination is considered to beone of the most eective means of protecting
individuals and populations from the risks associated with exposure to various
pathogens. The COVID-19 pandemic, caused by the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), aected people of all ages worldwide. In
response, several pharmaceutical companies rapidly leveraged their resources to
develop vaccines within a very short period of time, leading to the introduction
of new, improved, and combination vaccines for community-wide immunization.
This review aims to provide a summary of the available literature on the ecacy
and safety of COVID-19 vaccines in the pediatric population ranging from 0
to 18 years. An analysis of recent published studies reveals that the majority of
clinical trials have reported a sustained immune response following COVID-19
vaccination in children across various age groups worldwide. The majority of
the authors highlighted the eectiveness and safety of immunization schedules
in children and adolescents. The population-level ecacy of this vaccination
remains to be determined, provided that the benefits outweigh the potential
risks. Long-term side eects must still bemonitored to enable the development
of safer and more eective vaccines for future pandemics.
KEYWORDS
vaccine, COVID-19, SARS-CoV-2, ecacy, safety, children
1 Introduction
e COVID-19 infection, caused by the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), emerged at the end of 2019in Wuhan, China, and rapidly spread to all
continents. is virus aects people of all ages worldwide and was declared a pandemic by the
World Health Organization (WHO) on 11 March 2020 (1). e global impact of COVID-19,
with hundreds of millions of conrmed cases and over 9 million fatalities, has spurred
signicant scientic interest. Researchers have focused on understanding the pathogenesis of
the disease, its epidemiology, and how it varies with age or pre-existing clinical conditions.
ere is also a strong emphasis on exploring methods of prevention and treatment.
Vaccination is considered to beone of the most eective interventions for individual and
collective protection of the population against the risks caused by exposure to various
pathogens. Vaccination eorts at local, regional, national, and global levels have consistently
demonstrated their benets over time, eradicating life-threatening diseases, reducing
OPEN ACCESS
EDITED BY
Maarten Jacobus Postma,
University of Groningen, Netherlands
REVIEWED BY
Larry Ellingsworth,
Novavax, Inc., UnitedStates
Jacques L. Tamuzi,
Stellenbosch University, SouthAfrica
*CORRESPONDENCE
Ancuta Lupu
anca_ign@yahoo.com
Vasile Valeriu Lupu
valeriulupu@yahoo.com
†These authors have contributed equally to
this work
RECEIVED 24 February 2024
ACCEPTED 24 December 2024
PUBLISHED 29 January 2025
CITATION
Azoicai AN, Miron I, Lupu A, Alexoae MM,
Starcea IM, Alecsa M, Lupu VV, Danielescu C,
Nedelcu AH, Salaru DL, Dragan F and
Ioniuc I (2025) COVID-19 vaccination:
challenges in the pediatric population.
Front. Public Health 12:1390951.
doi: 10.3389/fpubh.2024.1390951
COPYRIGHT
© 2025 Azoicai, Miron, Lupu, Alexoae,
Starcea, Alecsa, Lupu, Danielescu, Nedelcu,
Salaru, Dragan and Ioniuc. This is an
open-access article distributed under the
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that the
original publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or reproduction
is permitted which does not comply with
these terms.
TYPE Review
PUBLISHED 29 January 2025
DOI 10.3389/fpubh.2024.1390951
Azoicai et al. 10.3389/fpubh.2024.1390951
Frontiers in Public Health 02 frontiersin.org
morbidity, and limiting the consequences of infections that
determined suering, disability, and death in the pre-vaccine era (such
as diphtheria, tetanus, whooping cough, poliomyelitis, measles,
rubella, and so on). e proof of these eects is also represented by the
fact that the number of deaths caused by vaccine-preventable diseases
decreased from 0.9 million in 2000 to 0.4 million cases reported in
2010 (2, 3).
A key benet of vaccination programs is the induction of
population-wide immunity, oen referred to as “herd immunity.” is
immunity protects the community against disease through widespread
vaccination, resulting in a decrease in pathogen circulation within that
community (3). Among various medical interventions involving
biologically active medications, the protection of an entire community
is uniquely achievable through extensive vaccination eorts (4, 5).
Unvaccinated individuals can benet from “herd immunity,” which
creates a potential ethical issue of “free-riders.” ese are people who
gain the advantages of vaccination programs without personally
taking on any of the risks associated with receiving the vaccine
directly (3, 4).
e lack of high-quality research hampers a comprehensive
understanding of the post-acute and long-term consequences of
COVID-19. By standardizing the denitions and harmonizing
research, diagnosis, and treatment approaches for long-term COVID-
19, we can improve the coherent collection of national and
international data. is would enable better estimates of incidence,
prevalence, and risk factors tailored to dierent age groups. ere is a
critical need for large, coordinated longitudinal studies to explore the
various aereects of SARS-CoV-2 infection in children and
adolescents. While relatively few studies have targeted this
demographic, patient support groups have reported that many
children suer from the lingering eects of COVID-19. High-quality
evidence is urgently needed, and this could be facilitated by
conducting controlled trials that account for societal variables.
Additionally, robust case–control studies are essential for
identifying sources and risk factors for various long-term COVID-19
conditions, which will aid in the development of targeted interventions
and support mechanisms.
2 Methods
A substantial body of literature has emerged on surveillance
advancements during the COVID-19 pandemic. While wastewater
epidemiology has seen extensive research, topics such as health equity
for racial and ethnic minorities are less studied. In areas with extensive
research, conducting systematic reviews may bethe logical next step.
Conversely, in elds where knowledge is scarce, further research is
essential to advance monitoring in the post-pandemic era.
Additionally, the widespread implementation of these surveillance
techniques necessitates a comprehensive analysis of potential
consequences, including ethical, legal, security, and equity
implications, as highlighted by numerous studies (5). Our literature
search was conducted using Medline and Medscape, focusing on
articles published from 2019 to 2024 with keywords including
“pandemic,” “SARS-COV2 infection,” “vaccine,” “children,” “safety,”
and “ecacy.”
Researchers’ ndings support the development of
multidisciplinary collaborative rehabilitation programs for younger
populations impacted by COVID-19 and the deployment of
monitoring systems to monitor the health eects of the virus. ere
are meta-analyzes, cross-sectional studies, reviews, and prospective
studies to prove that vaccination in early age groups can reduce the
burden of COVID-19 infection. To close the gap between research
results and clinical application in this discipline, it is critical that
non-physical outcomes begiven top priority in future attempts (6).
Our objective is to oer suggestions for lling in the knowledge
gaps on the long-term eects of COVID-19 on children. Priorities for
studying the eects of COVID-19 on children’s bodies, minds,
emotions, and social interactions must be determined within a
systems framework and coordinated on a national and worldwide
scale. Wecall on national and international funding organizations to
promote coordination eorts between families impacted by long-term
COVID-19 and experts such as pediatricians, epidemiologists,
rehabilitation clinicians, psychologists, psychiatrists, researchers, and
public health experts. A dynamic assessment of the eects of
prolonged COVID and the care required for children with this illness
may be made easier by longitudinal repeated examinations of
representative samples of children and adolescents with a diagnosis of
SARS-CoV-2 infection and matched control individuals. is type of
research design could also help clinicians to discriminate between
short- and longer-term outcomes of the condition and the impact, as
well as provide evidence-based proles of individuals who are aected
by long-term COVID-19, identify those at higher risk, and inform
targeted interventions to improve long-term outcomes.
Children may serve as a reservoir for the virus and spread it, even
if the majority of them are asymptomatic or just mildly aicted by
COVID-19 infections. e nancial burden and vaccine accessibility
are crucial factors in requiring the COVID-19 vaccine. Before
vaccinations are required, a number of ethical issues also need to
beconsidered. Unknown are the vaccine’s ecacy and safety for kids,
their vulnerability to infection, their part in the disease’s spread, and
the anticipated advantages. Moreover, religious beliefs, parental
hesitancy, media involvement, and anti-vaccination campaigns might
also beconsidered real challenges in children’s COVID-19 vaccination.
3 COVID-19 vaccines
is infection is characterized by clinical and evolutionary
polymorphism, which is inuenced by the viral variants that emerge
over time (such as the alpha, delta, and omicron strains) and the age
at which the infection occurs. is variability contributes to skepticism
regarding the vaccination of children (1). is situation is principally
based on the limited knowledge about advancements in developing
more eective and less harmful vaccines, and this is again a reason for
which authors should focus on proving the ecacy of vaccines and the
lack of side eects. en, there is the deep-rooted idea that the best
immunization is provided by the disease. erefore, the human body
should beallowed to face the disease (7), a principle that has still not
been proved in the case of COVID-19 infection.
For example, the pediatric population evaluated in studies and
meta-analyzes is inferior to cohorts of adult subjects, which implies a
greater degree of extrapolation of the obtained data but also
necessitates continuous eorts. e lack of studies focusing on the
ecacy and safety of COVID-19 vaccines for children and infants
complicates eorts to vaccinate these population groups. While
Azoicai et al. 10.3389/fpubh.2024.1390951
Frontiers in Public Health 03 frontiersin.org
COVID-19 vaccination in adults was reported to decrease in
percentage, children and young people (CYP) registered higher rates
of vaccination in the past 4 years (8).
e main benets of COVID-19 vaccination for children include
overcoming potential side eects and achieving immunity.
Nevertheless, even minor vaccination risks need to beconsidered, as
the likelihood of serious illness in otherwise healthy children is very
low. e majority of the potential benet of vaccination in preventing
serious illness and/or PIMS-TS/MIS-C has been diminished because
of pre-existing immunity to infection and decreased incidence of
hyper-inammatory response as a result of both viral evolution and
pre-existing immunity. Any possible advantage in stopping the spread
of viruses is negligible and transient. If there is already a high level of
community immunity due to infection, then any benets from
temporarily boosted immunity for otherwise healthy children may
beoutweighed by the high nancial and opportunity costs associated
with starting new vaccination programs. For children with signicant
comorbidities, there is a much larger absolute reduction in risk
provided by periodic vaccination, which is the basis of the majority of
current national public health recommendations (9).
Possible (or probable) post-vaccination reactions, in the context of
the use of biologically active vaccines, are currently reduced as a result
of the evolution of knowledge in the eld of modern vaccinology. e
security measures adopted in the case of the production and use of
vaccines, as in fact of any procedure or medicinal product that is
applied to an individual or a large population, provided safety for the
recipient. Developing vaccines with high immunogenicity and low
reactogenicity characteristics has determined an extremely limited
possibility of installing such reactions under the condition of
compliance with specic regulations and protocols, which are necessary
in the case of application of preventive or therapeutic action (10, 11).
e increasingly advanced knowledge of the mechanisms of the
vaccines, as well as the circumstances that allow the minimization of
risks, is a priority for the medical world that has the duty to make known
these scientic truths in order to regain the trust of the population in a
measure that has demonstrated, over time, to be benecial to the
individual and the human community (8, 12). ere has to behigher
compliance from the caregivers (parents, family doctors, specialists) in
order to protect young patients against COVID-19 infection, which
proved to belife-threatening in children’s pathology (13).
e majority of the studies initially stated that there is a low
susceptibility to SARS-CoV-2 infection in children. e disease also has
a generally milder course than in adults, with a low percentage of severe
cases and usually burdened by an underlying chronic pathology (chronic
pulmonary conditions such as cystic brosis, tuberculosis, pulmonary
malformations, ciliary dyskinesia, cardiovascular malformations, genetic
syndromes, oncological, and renal diseases) (13, 14). e phenomenon
could beexplained by several mechanisms. One would bethe action of
the innate immune response, the rst line of defense against pathogens,
which tends to be more active in children. Paradoxically, another
explanation could bethe immaturity of the children’s immune system,
which is probably not able to sustain the cytokine storm similar to that
observed in the adult population. Also, the dierent distribution of
membrane ACE2 receptors in adults and children with a lower receptor
binding capacity could beresponsible for the attenuated symptoms in
their case, as well as a higher plasma concentration of soluble ACE2
receptors, the particular interaction with these receptors, thus being able
to limit their replication in tissues (15, 16).
Multiple trials have evaluated the ecacy and safety of COVID-19
vaccines in both healthy adults and patients with comorbidities (14–
19). Similarly, vaccination against coronavirus can prevent serious
outcomes or hospitalization following the natural infection (20). Of
note, children and adolescents had their education, safety, and mental
and physical wellness negatively aected during the pandemic,
making vaccination crucial for them to avoid further isolation (21).
All children and adolescents should beconsidered for COVID-19
vaccination for their own protection against the infection and its
dierent outcomes, and more importantly, because they are part of the
COVID transmission cycle, thus being carriers and serving as a
reservoir of disease for elders (parents, grandparents) (8–12, 22–24).
Several clinical trials supported the favorable immune response,
eectiveness, and safety proles of COVID-19 vaccines in healthy
children and adolescents and even in those with underlying medical
conditions (25–28). In almost all studies, authors aimed to collect data
regarding the immunogenicity, ecacy, and safety of COVID-19
vaccines to guide healthcare workers and families in vaccinating the
younger population.
Patients with autoimmune diseases or immunodeciencies have
a higher risk of COVID-19 infections, hospitalization, and death than
the general population and are a priority for vaccination (29). Due to
a lack of information, medication side eects, and the possibility of
triggering severe side eects in those special categories of patients,
both doctors and caregivers are oen reserved in recommending and/
or accepting COVID-19 immunization.
Juvenile idiopathic arthritis (JIA) is the most common pediatric
rheumatic disease, the burden within young children and adolescents
being related to infectious risk factors and autoimmunity as a trigger.
is is the reason that makes preventing viral infections the most
eective tool in controlling the disease. Authors have been challenged
in proving the ecacy and the real need for COVID-19 vaccination for
those specic population categories. An observational study that
compares the immunogenicity and the safety of the Pzer COVID-19
vaccine in patients with JIA in the age group between 12 and 16years
and a group of healthy controls shows no statistically signicant
dierences in the average levels of antibodies in the patients and
controls, in line with other studies of Pzer immunogenicity in
adolescents with JIA. An important matter is that of immunosuppressive
therapy, and this is why methotrexate was discontinued during the
weeks of the rst and second vaccine inoculations. Non-steroidal anti-
inammatory drugs (NSAIDs) and biological drugs were not
discontinued while treating the patients for COVID-19 (30). e
authors also observed that patients with systemic JIA produced lower
antibody titers than patients with other types of JIA (31). It’s been
underlined in those ndings the fact that COVID-19 vaccination does
not interfere with the JIA treatment and does not exacerbate symptoms
of the disease. Authors have proven, in fact, that vaccination protects
against developing COVID-19in children with JIA (32).
Since the beginning of the pandemic, children with primary
immune deciency (PID) have been the main category of concern
(33). Before the worldwide extension of the viral strains of COVID-19,
children with primary immune deciencies were also at very high risk
of acquiring and manifesting infections, making them a special
category of eligible candidates for the majority of the vaccines.
Transplantation, substitutive therapy, specic medication, young age,
and comorbidities were the main concerns in having the PID children
vaccinated against COVID-19. Questions were raised regarding the
Azoicai et al. 10.3389/fpubh.2024.1390951
Frontiers in Public Health 04 frontiersin.org
benets or the risks for those special patients. Although PID is among
the main preexisting conditions associated with COVID-19 infection
in children, patients with phagocytic or antibody defects or children
with combined PID who have already been transplanted can develop
mostly asymptomatic or mild COVID-19 (34, 35). e authors agreed
on the need for pediatric patients with primary immune deciency to
bevaccinated, thus reducing the risks of severe COVID-19 illness and
death. is most vulnerable population must be sheltered from
infection, taking into consideration that the immune response to
SARS-CoV-2 vaccines may dier in people with primary immune
deciency. is is why an individual approach is required, and specic
organizations, such as the Centers for Disease Control and Prevention
(CDC), have developed specic guidance, COVID-19 vaccination
being the primary prevention strategy (36), along with specic and
reliable therapies that have been approved in the case of those patients.
PID pediatric patients may also develop prolonged or severe
forms of COVID-19 infection, and it is mandatory to dene their
immune response to the disease. us, the Committee of Experts on
Primary Immunodeciency has included vaccination both as a
diagnostic tool (to assess the specic antibody response to protein and
polysaccharide antigens) and as a means of prevention (37). e
response to COVID-19 infection by developing antibodies was
assessed later on, and the ecacy of vaccination relied on the detection
of specic antibodies against SARS-CoV-2 antigens. In the general
population, the level of neutralizing antibodies is correlated to
protection, and mRNA vaccination generated robust humoral and
cellular immune memory to SARS-CoV-2 for at least 6 months
following mRNA vaccination (32). In particular, patients with PID
may not beable to maintain this immunogenicity over time. However,
even in healthy individuals, the antibody response may wane over
time or may not bedetectable in patients with antibody deciency (37).
For children and adolescents with allergic conditions such as
wheezing and asthma, there were concerns regarding the safety of
vaccination, given the risk of having an anaphylactic reaction to a
COVID-19 vaccine, even though severe allergic conditions were not
noted in a pediatric population. A systematic review of the literature
noted that the incidence of an allergic reaction to an mRNA-based
COVID-19 vaccine is 7.91 cases per million doses (95% CI 4·02–
15·59) (40), a very low risk if wetake into consideration the benet of
protection. ere were no reported anaphylactic fatalities related to
COVID-19 vaccination, and the local allergic reactions resolved
rapidly without long-term sequelae. Furthermore, revaccination aer
an initial allergic reaction was well tolerated within those patients (41).
Anaphylaxis is unpredictable, so a prudent approach is advisable,
such as allergic evaluation in case of previous systemic reactions to
vaccines or drugs. Risk assessment of allergic reactions to COVID-19
vaccines is useful in limiting contraindications to vaccination and
obtaining medical recommendations and parental consent. All
vaccine centers should follow international and national guidelines,
and doctors should be trained in preventing, recognizing, and
managing post-vaccinal anaphylaxis (42).
4 Immunogenicity of COVID-19
vaccines in children
Immunogenicity concerns regarding children, including those
with chronic illnesses as well as for healthy individuals, have been in
focus since the beginning of the pandemic. e primary concern was
whether the immunogenicity achieved with one or multiple vaccine
doses varies signicantly based on age, medical history, or immune
response in children. Specialists must consider factors such as age
group, immune status, comorbidities, chronic illnesses, and/or
immunosuppressive conditions. It can bestated that there still is an
urgent need for continuous surveillance and extensive studies to assess
the real status of immunogenicity achieved with vaccination versus
naturally acquired antibodies (43). e dierences between the
population groups that were observed in extensive studies can explain
the lack of protection against further infection in some categories of
individuals with one or multiple vaccine protections (such as in the
case of immune-decient children).
Authors reported approximately 99% serologic response to the
mRNA-1273 Moderna vaccine in people aged 12–17 years old,
compared to a 98.6% response in younger adults—according to Ali et
al. (44). Furthermore, the ndings stated that the neutralizing
antibody titers in younger ages (children) showed no inferiority when
compared to those in older patients.
Frenck et al. (45) conducted a randomized clinical trial to assess
the eects of the BNT162b2 (Pzer) vaccine in children and
adolescents aged 12–15 years. e authors found these subjects
developed higher post-vaccination antibody titers compared to
vaccinated younger adults and the control group. Other authors (46,
47) revealed that nearly all (99.2%) of Pzer-vaccinated children aged
5–11 years achieved a satisfactory serologic response 1 month aer
receiving the second dose.
ese ndings support the notion that immunization should
be considered for early age groups, as many studies suggest that
younger children tend to produce higher rates of antibody production.
is may bedue to the innate immune system, which is more active
in infants and young children, enabling them to develop higher titers
of antibodies and maintain these at protective levels for extended
periods. However, the paucity of extensive studies conrming the
safety of vaccinations in these age groups remains a concern, oen due
to parental hesitancy to provide consent.
5 Ecacy of COVID-19 vaccines in
children and adolescents
e benet of immunization was demonstrated in the adult
population, as the levels of morbidity and mortality due to COVID-19
infection dramatically decreased worldwide. Regarding passive
immunization in young children, there is still controversy among
authors who conducted studies centered on the real need for
vaccinating children. e majority of the studies initially stated that
there is a low susceptibility to SARS-CoV-2 infection in children, the
disease also having a generally milder course than in adults, with a low
percentage of severe cases and usually burdened by an underlying
chronic pathology (48).
On the other hand, several studies showed the need for children
and adolescents’ COVID-19 vaccination—rst for the protection
against the infection and second because they are part of the
COVID-19 transmission cycle. Children represent important carriers
of the disease, regardless of the fact that they express the symptoms
more or less prominently, thus serving as a reservoir of disease for
elders, in which the outcome may be fatal. Isolation, lack of
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socialization methods, and mental and behavioral changes within the
pandemic were issues that conducted authors in providing the
population with “pro” and “con “arguments regarding the ecacy of
vaccination in children and adolescents and the long-term protection
against the infection.
e ecacy of the COVID-19 vaccine in children aged 5–11 years
was reported to benearly 91% aer the second dose, according to
Frenck et al. (45), using the Pzer vaccine. Moreover, the authors
noted a remarkable ecacy rate of 100% in individuals aged
12–15 years (45). In another study assessing the ecacy of the Pzer
vaccine in adolescents aged 12–18 years, only two patients out of 57
participants contracted COVID-19 aer being immunized: one
patient tested positive before receiving the second dose, and the other
46 days post-second dose (46).
A particular group of potential vaccine recipients—those with
underlying medical conditions, chronic illnesses, or immunodeciency
due to chemotherapy regimens, as well as children with innate
immunodeciencies—requires careful evaluation of vaccine ecacy.
e benecial eects on these children and adolescents have been
assessed in studies encompassing multiple vaccine types and
considering various age groups.
Adolescent patients with solid tumor malignancies who completed
the full Pzer vaccine immunization schedule were not found to beat
risk of developing COVID-19 infection (41). In studies involving
other vaccine types eligible for the population under 21 years of age,
such as Moderna, CoronaVac, and ZyCov-D, ecacy rates of 93.3,
65.5, and 100% protection against COVID-19 infection were reported
among participants aged 12–19 years, respectively (46). Further
extensive studies on additional vaccine types, including Sinopharm
and COVAXIN (NCT04918797), also suggested high protection
ecacy against COVID-19in the 2–18-year-old age group (46).
ere is also the question of whether ecacy should bediscussed
in terms of age group, as long as innate immunity may bean advantage
in obtaining higher levels of protective antibodies in young children.
Recently, a group of Italian authors conducted a retrospective
population study, assessing vaccine ecacy against SARS-CoV-2
infection and the severe COVID-19 infection rates (dened as an
infection leading to hospitalization or lethal outcome) by linking the
national COVID-19 surveillance system and the national vaccination
registry. All Italian children aged 5–11 years without a previous
diagnosis of infection were eligible for inclusion. e authors followed
up with the patients over a 4-month period of time, relying on
unvaccinated children as the reference group. Furthermore, the
authors estimated the vaccine ecacy in those participants who were
partly vaccinated (one dose) and in those who were fully vaccinated
(two doses) (47).
e results showed that 35.8% of children aged 5–11 years
included in the study had received two doses of the vaccine, and only
4.5% had received only one dose; 59.6% of all age groups represented
the children who were unvaccinated. e results were not promising,
with multiple cases of severe COVID-19 (627 hospitalizations, 15
admissions to intensive care units, and two deaths), as well as many
mild infections. Overall, authors assessed the vaccine ecacy in the
fully vaccinated group as being only 29.4% against SARS-CoV-2
infection and not higher than 411% against severe COVID-19,
whereas vaccine ecacy in the partly vaccinated group was rather
similar, with 27.4% ecacy against SARS-CoV-2 infection and 38.1%
against severe COVID-19 (47). To sum up, the results demonstrated
that vaccination against COVID-19in children aged 5–11 years in
Italy had, in fact, lower eectiveness in preventing SARS-CoV-2
infection and severe COVID-19 than in individuals aged 12 years and
older. Eectiveness against infection appears to increase up to 14 days
following immunization, with a decrease aer completion of the
current primary vaccination cycle of 43–84 days (47).
6 Safety of COVID-19 vaccines in
children and adolescents
Regarding the safety and security of all vaccines, there is a
comprehensive and lengthy chain of surveillance measures and
regulations established in each region or country. Initially, it is
determined whether the new vaccine can undergo evaluations to
receive the license. e special accredited committees for the
supervision and licensing of a vaccine, in collaboration with the
manufacturers, monitor the safety and ecacy of the vaccine through
a strategy based on national or international laws and regulations.
European regulation on the authorization and population use of
medicinal devices for human use includes vaccines among
immunological biological products. e evaluation of a vaccine is
carried out identically to that of any medicine. e stages are laborious
and take a long time to becarried out. ey are completed by drawing
up documentation that includes the results of clinical and
pharmaceutical studies, particularly those related to the
product’s safety.
Improved vaccine safety monitoring and the timely, accurate, and
transparent disclosure of safety ndings were crucial aspects of the
COVID-19 response during the US COVID-19 pandemic
immunization program. is comprehensive approach included
clinical consultations, long-term follow-up on individual cases of
myocarditis aer immunization, both active and passive surveillance,
and monitoring of pregnancy and infant outcomes. e most ecient
methods for disseminating the latest information to stakeholders and
the public involved updating agency websites, engaging through social
media, presenting ndings to federal advisory bodies, and publishing
safety results in scientic journals (48, 49).
Safety studies have been conducted for vaccines that have been
approved for years and decades, thus guaranteeing the possibility of
long-term surveillance of subjects. e COVID-19 pandemic was the
turning point in drawing a new era for “fast-forward” developing and
testing vaccines. A key point considered to becrucial for controlling
the virus transmission and pandemic annihilation was the possibility
of initializing vaccine development studies. is was the reason for
observing and assessing early side eects even at the same time as
actual immunization and not waiting longer for outcomes in vitro
studies. Several pharmaceutical companies had the opportunity and
the industrial means to develop a vaccine quickly, releasing new,
improved, and combined vaccines for community immunization
(50, 51).
Reported adverse reactions were mild to moderate and self-
limiting, as long as the current studies have shown a signicant
percentage of parents willing to vaccinate their children and
adolescents against the new coronavirus. e most common adverse
reactions following immunization comprised injection site pain and
erythema, headache, fatigue, fever, and chills (52–54), nothing more
than in the case of other studied vaccines.
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Frontiers in Public Health 06 frontiersin.org
e authors had the opportunity to assess the side eects in a
specic and distinct group within the community. In the case of
adolescents and young adults (aged 16–25 years) residing in a long-
term care facility who received the Pzer vaccine, 84% experienced
mild adverse reactions aer the rst dose, and 74.2% reported similar
eects following the second dose. ese reactions included discomfort,
nausea/emesis, diarrhea, fever, chills, headache, and skin erythema at
the inoculation site (54).
e Pzer vaccine was administered to pediatric patients and
young adults with juvenile inammatory arthritis (JIA) aged
16–21 years, with no reported exacerbation of the chronic disease,
indicating a good safety prole for this particular group (54). However,
transient increases in agitation and changes in seizure patterns,
specically cluster seizures, were observed in recipients aged
12–15 years old with underlying neurologic and mental conditions.
ese observations highlight the need for further monitoring of post-
immunization side eects in these vulnerable groups (53, 54).
Recent extensive studies have reported an increased incidence of
myocarditis and pericarditis aer COVID-19 vaccination, particularly
among male adolescents and young adults, raising major global
concerns. For instance, in Israel, ve male patients with a median age
of 23 developed myocarditis aer receiving the BNT162b2 vaccine
(55). Additionally, in the United States, eight male adolescents
presented with myocarditis within 4 days of receiving a dose of the
BNT162b2 vaccine, as noted by the authors (56). Another report
highlighted a series of 25 children aged 12–18 years diagnosed with
probable myocarditis aer COVID-19 mRNA vaccination at eight US
centers between May and June 2021. ese cases did not show any
clinical or functional impact post-treatment. Treatment approaches
varied: three cases were managed with non-steroidal anti-
inammatory drugs, while four patients received a combination of
intravenous immunoglobulin and cortisone therapy to control the
condition (57).
Recent reports have demonstrated that multisystem inammatory
syndrome (MIS) can occur aer SARS-CoV-2 vaccination, now
identied as “MIS-V” rather than “MIS-V.” An instance of such
symptoms was documented in an 18-year-old adolescent following the
administration of the Pzer-BioNTech BNT162b2 vaccine (58). e
primary clinical features mirrored those observed during the acute
phase of infection, including fever lasting for 3 consecutive days, mild
to moderate pericardial eusion, elevated levels of CRP, NT-BNP,
troponin T, and D-dimers, which is evidence of cardiac involvement,
and positive IgG SARS-CoV-2 antibodies, which helps to establish a
link between the vaccination and the observed symptoms (58).
7 COVID-19 vaccination in MIS-C
patients
Multisystem inammatory syndrome developed aer COVID-19
infection represents a milestone for developing further medication and
prophylactic therapy, both for adults and especially for children, in which
the outcome was severe (even lethal in some cases). Study data regarding
adverse reactions aer COVID-19 vaccination in adult pediatric patients
with a history of multisystem inammatory syndrome (MIS-C) are
limited. is lack of safety and ecacy data in this specic population
may cause limited approval for vaccination from healthcare professionals
and hesitancy and concern for caregivers and parents. ere is an interest
in applying most of the study designs to a wide population of children
when the analysis design and the reported data’s applicability can
be extended. erefore, assessing the results and conclusions would
appear to bemore trustworthy.
MUSIC is a multicenter, cross-sectional study including 22 North
American centers participating in a National Heart, Lung, and Blood
Institute, National Institutes of Health-sponsored study, Long-Term
Outcomes Aer the Multisystem Inammatory Syndrome in
Children. e pediatric population with a prior diagnosis of MIS-C
that appeared to beeligible for COVID-19 vaccination at the time of
enrolling (age ≥ 5 years; ≥90 days aer MIS-C diagnosis) were
surveyed over a period of 3 months regarding COVID-19 vaccination
status and reported adverse reactions (59). e authors were trying to
assess whether MIS-C would bea condition to take into consideration
when establishing the need, the benet, or the actual risk for
vaccination. Patients were also randomized based on age group,
ethnicity, and medication intake.
Almost half of all the 385 vaccine-eligible patients surveyed, 185
(48.1%), received at least one vaccine dose; the majority of vaccinated
patients (73.5%) were male, at a median age of immunization of
12 years. Among vaccinated patients, there were mostly white
children, as well as a signicant percentage of Asian, Hispanic, and
Black ethnicity. e median time lapse from the initial moment of
MIS-C diagnosis to the rst vaccine dose inoculation was almost
9 months. Out of them, 31 patients (16.8%) received one vaccine dose,
142 (76.8%) received two doses, and 12 (6.5%) received all three doses
of the vaccine. It is important to observe that almost all patients
received the BNT162b2 vaccine—98.9% (59).
Minor adverse reactions were observed in almost half of the study
group—48.6%. e complaints most oen included arm soreness and/
or fatigue, which did not require medical attention. However, in 32
patients (17.3%), adverse reactions were treated with medications,
most commonly for the fever and the pain, using either acetaminophen
or ibuprofen. Only four patients were addressed for medical
evaluation, but none required testing or hospitalization. Moreover,
neither of the patients included in the study developed an MIS-C
symptomatology aer vaccination nor cardiovascular events, which
are a key point in assessing the safety of immunization in young
children (59).
e authors did not report any patients with serious adverse
events, such as myocarditis or recurrence of MIS-C (59), proving that
there were no severe adverse events aer COVID-19 vaccination.
Findings suggest that the safety prole of COVID-19 vaccination
administered at a time-lapse of at least 90 days following MIS-C
appears to besimilar to that assumed in the general population.
Zambrano et al. (60) compared the odds of being fully vaccinated
with two doses of the BNT162b2 vaccine (≥28 days before hospital
admission) between MIS-C case patients and hospital-based controls
who tested negative for SARS-CoV-2. Authors examined those
associations by age group, timing of vaccination, and periods of Delta
and Omicron variant predominance (60). is study was conducted
across 29 hospitals in 22 US states in the Centers for Disease Control
and Prevention (CDC)–funded Overcoming COVID-19 (OC-19)
pediatric vaccine eectiveness network. Clinical outcomes among
MIS-C patients for those requiring ICU admission, vasopressor
support, and noninvasive or invasive mechanical ventilation were
clearly in favor of those who received a complete vaccination schedule.
ose ndings are also supported by a comparison of MIS-C cases
resulting in life support or death between vaccinated and
unvaccinated patients.
Azoicai et al. 10.3389/fpubh.2024.1390951
Frontiers in Public Health 07 frontiersin.org
In comparison, Cortese etal.., out of a cohort of 77 patients, 58
children were identied who developed MIS-C within 90 days aer
receiving a COVID-19 vaccine and had evidence of past or recent
SARS-CoV-2 infection. Additionally, four children met the MIS-C
criteria but had no evidence of SARS-CoV-2 infection. e authors
were unable to conclusively determine whether the COVID-19
vaccination contributed to the MIS-C cases identied in the study
group. is uncertainty was partly due to the expectation of an
increase in MIS-C cases associated with the Omicron variant of SARS-
CoV-2, which coincided with the availability of the COVID-19
vaccine for this age group approximately 5–6 weeks prior to the
enrollment of cases in the study (61).
Table1 summarizes the studies regarding the ecacy and safety
of vaccination in children.
Regarding the reason for conducting studies in pediatric age, the
majority of the authors state that children’s vaccination against
COVID-19 is a moral obligation, as well as a practical need in
reducing the burden of the infection, as long as the safety of the
vaccines is to beassessed (62). Parental consent is sometimes impaired
by the lack of studies in this eld. According to the majority of the
current literature, our manuscript highlights the crucial importance
of children’s vaccination against COVID-19 and the immunogenicity
and safety of the vaccines at pediatric age (63).
According to the major topic of this literature review (COVID-19
vaccines, immunogenicity of COVID-19 vaccinations in children,
ecacy of COVID-19 vaccines in children and adolescents, safety of
COVID-19 vaccines in children and adolescents), the authors created
a conceptual table (Table2) that can beused in the future to produce
better, safer, and more eective vaccines for children and adolescents
to mitigate the impact of a potential new pandemic (45, 64, 65).
8 Conclusion
Rapid advancements in research on SARS-CoV-2 infection and
COVID-19 immunization have led to recommendations from
professional societies arming the safety and ecacy of vaccinating
children and adolescents. e emergence of new variants of SARS-
CoV-2 (alpha, delta, omicron) had increased transmissibility and
made it clear that acquiring herd immunity would berequired to
control the pandemic. Coinfection or superinfection comorbidities
(viral, bacterial, fungal) equate to a poor prognosis for the pediatric
patient. Additionally, younger age groups oen exhibit more complex
immunological backgrounds, including primary and secondary
immunodeciencies. When vaccinating younger patients, it is crucial
to consider the epidemiological context in which acute COVID-19
infection may occur, especially during the seasonal circulation periods
of other viral agents such as inuenza, parainuenza viruses, and
respiratory syncytial viruses.
e costs associated with pediatric primary care, emergency
services, and possible hospital admissions due to severe clinical
manifestations, as well as direct or indirect costs for long-term care of
children who experience recurrent COVID-19 infections or develop
MIS-C, pose a signicant economic burden. is burden is substantially
higher than the cost of maintaining consistent and comprehensive
immunization eorts. Community-wide epidemiological surveillance
of COVID-19 infections and immunization in the pediatric population,
along with the implementation of specic monitoring protocols,
tracking of recurrent hospitalizations due to COVID-19-related
respiratory infections, and conducting medium- and long-term
follow-up in patients with MIS-C symptoms, will provide crucial data
for the implementation of extended prophylaxis.
However, ethical and legal considerations regarding the
vaccination of minors cannot beoverlooked, particularly in light of
ongoing debates in the scientic community about the inclusion of
children and young people in COVID-19 vaccine trials. Moreover, it
is essential that children, adolescents, and infants are included in
comprehensive studies that monitor, describe, and document any
adverse reactions following COVID-19 vaccination, especially in
patients with a history of MIS-C. ese measures are critical to
ensuring the safety and ecacy of vaccines for this vulnerable
population.
is review highlights that while the population-level eectiveness
of this specic vaccination remains to befully established, the global
benecial response generally outweighs the potential risks. Authors
have emphasized the importance of monitoring long-term side eects,
as this provides the opportunity to develop newer, safer, and more
eective vaccines, potentially including combined formulations, to
mitigate the impact of a future pandemic.
Author contributions
AA: Conceptualization, Investigation, Writing – original dra.
IM: Methodology, Supervision, Writing– review & editing. AL:
Investigation, Methodology, Writing – original dra. MMA:
Investigation, Soware, Writing– original dra. IS: Investigation,
Visualization, Writing– original dra. MA: Investigation, Soware,
Writing – original dra. VL: Conceptualization, Project
administration, Writing– review & editing. CD: Validation, Writing–
review & editing. AN: Validation, Writing– review & editing. DS:
Validation, Writing – review & editing. FD: Funding acquisition,
Validation, Writing– review & editing. II: Investigation, Methodology,
Writing– original dra.
Funding
e author(s) declare that no nancial support was received for
the research, authorship, and/or publication of this article.
Conflict of interest
e authors declare that the research was conducted in the
absence of any commercial or nancial relationships that could
beconstrued as a potential conict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their aliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may beevaluated in this article, or claim that may bemade by its
manufacturer, is not guaranteed or endorsed by the publisher.
Azoicai et al. 10.3389/fpubh.2024.1390951
Frontiers in Public Health 08 frontiersin.org
TABLE1 Current studies recommendations and evidence regarding the safety and ecacy of mRNA COVID-19 vaccines.
Authors Outline No. patients Ecacy/safety Age range Country/region
Opoka-Winiarska etal.
(32)
Children and adolescents
with JIA with remission
without treatment or on
long-term treatment—
cDMARDs or even
bDMARDs, can besafely
vaccinated for COVID-19
43 with JIA ++/++ 0–18 years Poland
Quinti etal. (37) Despite the antibody
deciency, T-cell immunity is
thought to belargely intact in
many patients with CVID, as
immunologists recommend
routine administration of
multiple vaccines, including
COVID-19 immunization
9 with PID +/+ 6–18 years and adult patients Italy
Krantz etal. (42) e majority of patients with
allergic reactions to mRNA
COVID-19 vaccines can
safely tolerate a second dose
of immunization
159 ++/++ 0–18 years Australia
Sacco etal. (47) Vaccine ecacy was 31%
(95% CI 9–48) at 14–82 days
aer completion of the
primary cycle in a sample of
1,364 children aged
5–11 years, very similar to
our estimate of 29.4% aer a
similar interval of 0–84 days
aer full vaccination
1,364 +/+ 5–11 years Italy
Myers etal. (49) V-safe contributed to the
CDC’s vaccine safety
assessments for FDA-
authorized COVID-19
vaccines by enabling near
real-time reporting of the
reactogenicity of the vaccines
9,342,582 ++/++ 0–18 years UnitedStates
Zambrano etal. (60) Vaccination with two doses
of vaccine is associated with
reduced risk of MISC C in
children
304 ++/++ 5–18 years UnitedStates
Cortese etal. (61) MISC C illness in children
aer COVID-19 vaccination
was below 1/million
vaccinated children
58 ++/++ 0–18 years
Tartof etal. (66) BNT162b2 BA.4/5 bivalent
mRNA vaccine against a
range of COVID-19
outcomes in a large health
system in the UnitedStates
proved eective in a test-
negative case–control study
24,246 ++/++ 0–18 years UnitedStates
(Continued)
Azoicai et al. 10.3389/fpubh.2024.1390951
Frontiers in Public Health 09 frontiersin.org
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TABLE1 (Continued)
Authors Outline No. patients Ecacy/safety Age range Country/region
Feldstein etal. (67) Bivalent mRNA COVID-19
vaccines are eective in
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infection in children and
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ecacy in a meta-analysis of
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410,2016 +/+ 6 months-18 years UnitedStates
Buoninfante etal. (69) Myocarditis associated with
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393 ++/++ 0–18 years Italy
TABLE2 Vaccine types, ecacy, and side eects in COVID-19 immunization in children.
Vaccine type Pfizer/BioNTech Moderna Novavax
Recommendation 6 m–4 y: 3-dose series ≥5 y: 1-dose 6 m–5 y: 2-dose series ≥6 y: 1-dose ≥12 y: 2-dose series
Ecacy and immunogenicity 75% (6 m–28 m)
71% (2–5 years)
90% (6–11 years)
95% (12–17 years)
51% (6 m–28 m)
36% (2–5 years)
88% (6–11 years)
92% (12–17 years)
No data available
No data available
No data available
79.5%
Side eects ↑↑ (6 m–28 m)
↑↑ (2–5 years)
↑ (6–11 years)
↑ (12–17 years)
↑ (6 m–28 m)
↑↑ (2–5 years)
↑ (6–11 years)
↑ (12–17 years)
No data available
No data available
No data available
↑ (12–17 years)
Immunization in MIS-C pediatric patients No data available No data available No data available
Azoicai et al. 10.3389/fpubh.2024.1390951
Frontiers in Public Health 10 frontiersin.org
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