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Pediatric Infectious Disease Group (GPIP) position paper on the immune debt of the COVID-19 pandemic in childhood, how can we fill the immunity gap?

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Abstract

Since the beginning of the COVID-19 pandemic, reduced incidence of many viral and bacterial infections has been reported in children: bronchiolitis, varicella, measles, pertussis, pneumococcal and meningococcal invasive diseases. The purpose of this opinion paper is to discuss various situations that could lead to larger epidemics when the non-pharmaceutical interventions (NPI) imposed by the SARS-CoV-2 epidemic will no longer be necessary. While NPIs limited the transmission of SARS-CoV-2, they also reduced the spread of other pathogens during and after lockdown periods, despite the re-opening of schools since June 2020 in France. This positive collateral effect in the short term is welcome as it prevents additional overload of the healthcare system. The lack of immune stimulation due to the reduced circulation of microbial agents and to the related reduced vaccine uptake induced an "immunity debt" which could have negative consequences when the pandemic is under control and NPIs are lifted. The longer these periods of "viral or bacterial low-exposure" are, the greater the likelihood of future epidemics. This is due to a growing proportion of "susceptible" people and a declined herd immunity in the population. The observed delay in vaccination program without effective catch-up and the decrease in viral and bacterial exposures lead to a rebound risk of vaccine-preventable diseases. With a vaccination schedule that does not include vaccines against rotavirus, varicella, and serogroup B and ACYW Neisseria meningitidis, France could become more vulnerable to some of these rebound effects.
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Pediatric Infectious Disease Group (GPIP) position
paper on the immune debt of the COVID-19 pandemic
in childhood, how can we ll the immunity gap?
Robert Cohen, Marion Ashman, Muhamed-Kheir Taha, Emmanuelle Varon,
François Angoulvant, Corinne Levy, Alexis Ryback, Naim Ouldali, Nicole
Guiso, Emmanuel Grimprel
To cite this version:
Robert Cohen, Marion Ashman, Muhamed-Kheir Taha, Emmanuelle Varon, François Angoulvant, et
al.. Pediatric Infectious Disease Group (GPIP) position paper on the immune debt of the COVID-19
pandemic in childhood, how can we ll the immunity gap?. Infectious Diseases Now, Elsevier, In
press, �10.1016/j.idnow.2021.05.004�. �hal-03231046�
Journal Pre-proof
Pediatric Infectious Disease Group (GPIP) position paper on the immune
debt of the COVID-19 pandemic in childhood, how can we fill the
immunity gap?
Robert Cohen Marion Ashman Muhamed-Kheir Taha Emmanuelle
Varon Franc¸ois Angoulvant Corinne Levy Dr Alexis Ryback Naim
Ouldali Nicole Guiso Emmanuel Grimprel
PII: S2666-9919(21)00112-3
DOI: https://doi.org/doi:10.1016/j.idnow.2021.05.004
Reference: IDNOW 4456
To appear in:
Received Date: 22 April 2021
Revised Date: 28 April 2021
Accepted Date: 10 May 2021
Please cite this article as: Cohen R, Ashman M, Taha M-Kheir, Varon E, Angoulvant F, Levy
C, Ryback A, Ouldali N, Guiso N, Grimprel E, Pediatric Infectious Disease Group (GPIP)
position paper on the immune debt of the COVID-19 pandemic in childhood, how can we fill
the immunity gap?, Infectious Diseases Now (2021),
doi: https://doi.org/10.1016/j.idnow.2021.05.004
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Pediatric Infectious Disease Group (GPIP) position paper on the immune debt of the
COVID-19 pandemic in childhood, how can we fill the immunity gap?
Robert Cohen1, 2, 3, 4, 5, Marion Ashman1, 6, Muhamed-Kheir Taha7, Emmanuelle Varon8,
François Angoulvant5, 9, 10, Corinne Levy1, 2, 3, 4, 5, Alexis Ryback1, 4, 5, Naim Ouldali1, 4, 5, 10, 11,
Nicole Guiso12, Emmanuel Grimprel5, 13
1ACTIV, Association Clinique et Thérapeutique Infantile du Val-de-Marne, Créteil, France
2Clinical Research Center (CRC), Centre Hospitalier Intercommunal de Créteil, Créteil, France
3Université Paris Est, IMRB-GRC GEMINI, Créteil, France
4AFPA, Association Française de Pédiatrie Ambulatoire, Saint-Germain-en-Laye, France
5GPIP, Groupe de Pathologie Infectieuse Pédiatrique, Créteil, France
6 Centre Hospitalier Intercommunal de Créteil, France
7 Centre National de Référence des Méningocoques, Institut Pasteur, Paris, France
8 Centre National de Référence des Pneumocoques, Centre Hospitalier Intercommunal de
Créteil, France
9Assistance Publique Hôpitaux de Paris, Department of General Pediatrics and Pediatric
Infectious Diseases, Necker-Enfants-Malades University Hospital, Université de Paris
10INSERM, Centre de Recherche des Cordeliers, UMRS 1138, Sorbonne Université, Université
de Paris, Paris, France.
11Assistance Publique-Hôpitaux de Paris, Department of general pediatrics, pediatric
infectious disease and internal medicine, Robert Debré university hospital, Université de Paris,
Paris, France.
12Institut Pasteur, Paris, France
13Service de pédiatrie, Centre Hospitalier Armand trousseau, Paris, France
Corresponding author: Dr Corinne Levy
ACTIV, 31 rue Le Corbusier, 94000 Créteil, France
E mail : corinne.levy@activ-france.fr, Tel : 00 33 1 48 85 04 04
Funding. No funding
Competing Interests: All authors declare no competing interests.
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Highlights
Since the beginning of the COVID-19 pandemic, a decreased incidence of many viral
and bacterial infections has been reported in children.
Non-pharmaceutical interventions limited the transmission of SARS-CoV-2 and
reduced the spread of other pathogens despite school re-opening.
The lack of immune stimulation due to the reduced circulation of microbial agents and
to reduced vaccine uptake induced an "immunity debt" with a growing proportion of
susceptible people.
Vaccination program delay and decreased viral and bacterial exposure lead to a
rebound risk of vaccine-preventable diseases.
As the French vaccination schedule does not include vaccines against rotavirus,
varicella, and serogroup B and ACYW Neisseria meningitidis, stronger epidemic
rebounds could be observed.
Abstract
Since the beginning of the COVID-19 pandemic, reduced incidence of many viral and bacterial
infections has been reported in children: bronchiolitis, varicella, measles, pertussis,
pneumococcal and meningococcal invasive diseases. The purpose of this opinion paper is to
discuss various situations that could lead to larger epidemics when the non-pharmaceutical
interventions (NPI) imposed by the SARS-CoV-2 epidemic will no longer be necessary.
While NPIs limited the transmission of SARS-CoV-2, they also reduced the spread of other
pathogens during and after lockdown periods, despite the re-opening of schools since June
2020 in France. This positive collateral effect in the short term is welcome as it prevents
additional overload of the healthcare system. The lack of immune stimulation due to the
reduced circulation of microbial agents and to the related reduced vaccine uptake induced an
"immunity debt" which could have negative consequences when the pandemic is under
control and NPIs are lifted. The longer these periods of "viral or bacterial low-exposure" are,
the greater the likelihood of future epidemics. This is due to a growing proportion of
"susceptible" people and a declined herd immunity in the population. The observed delay in
vaccination program without effective catch-up and the decrease in viral and bacterial
exposures lead to a rebound risk of vaccine-preventable diseases.
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With a vaccination schedule that does not include vaccines against rotavirus, varicella, and
serogroup B and ACYW Neisseria meningitidis, France could become more vulnerable to some
of these rebound effects.
Keywords. Covid-19 pandemic, VZV, Streptococcus pneumoniae, Neisseria meningitidis,
Bordetella, vaccination.
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Introduction
The current COVID-19 pandemic imposed a number of hygiene measures unprecedented in
history (distancing, masks, hand washing, reduced number of contacts, etc.). These personal
non-pharmaceutical interventions (NPI) contributed to limiting the transmission of SARS-CoV-
2, but they also reduced the spread of other pathogens. Thus, in hospital emergency rooms
and in private practices, the number of visits for community-acquired pediatric infectious
diseases decreased significantly, not only during the lockdown periods [1] but also beyond,
despite the re-opening of schools [2]. This includes numerous diseases such as gastroenteritis,
bronchiolitis (especially due to respiratory syncytial virus), chickenpox, acute otitis media,
non-specific upper and lower respiratory tract infections, and also serious ones such as
invasive bacterial diseases. These severe diseases due to Streptococcus pneumoniae,
Haemophilus influenzae b or Neisseria meningitidis are also associated with mucosal carriage
and human-to-human transmission through the respiratory tract. Conversely, no decrease in
the number of reported cases of Streptococcus agalactiae or urinary tract infections was
reported between January and June 2020 compared with the same period in 2018 and 2019.
This confirms that the reduction in reported S. pneumoniae, H. influenzae, and N. meningitidis
invasive diseases in 2020 reflects true decreases in incidence rather than underreporting [3].
This is not surprising because the transmission modes of these pathogens are often the same
as those of SARS-CoV-2 (essentially by large droplets, aerosols, and hands), often with a lower
transmissibility for many of them (based on lower R0). Personal NPIs imposed by the COVID-
19 pandemic were thus able to slow down transmission and contagion, and therefore disease
incidence. This positive collateral effect in the short term is welcome as it prevents additional
overload of hospital emergency rooms, wards, and intensive care units during the SARS-CoV-
2 epidemic. However, triggers of these invasive infections are early childhood infections, most
often viral, which are almost unavoidable in the first years of life. A lack of immune stimulation
due to personal NPI induces an "immunity debt" and could have negative consequences when
the pandemic is under control. Mathematical models suggest that respiratory syncytial virus
(RSV) and possibly influenza epidemics may be more intense in the coming years [4]. Finally,
through the possible role of "trained" innate immunity in the defense against infections and
a possible return of the hygienist theory, other consequences could be observed. For some of
these infections, negative consequences could be balanced by vaccinations (reinforcement of
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compliance with immunization programs in place, or even widening of vaccination target
populations).
The purpose of this paper is to discuss various situations that could lead to larger epidemics
when personal NPIs imposed by the SARS-CoV-2 pandemic are no longer necessary. We will
discuss in turn specific natural immunity to a number of viral and bacterial diseases, and other
possible immunological consequences of the various constraints imposed by the pandemic.
I. Specific (adaptive) immunity
I.A. Viral diseases
I.A.1. Varicella
In the absence of an immunization program, chickenpox is considered an unavoidable
childhood disease as all individuals contract varicella during their lives, most often in
childhood [5]. Late varicella onset, after puberty, is associated with greater severity, justifying
the recommendation to vaccinate individuals over 12 years of age who have not yet
contracted it in countries where general vaccination of toddlers is not implemented.
According to data from the French national agency for health (Santé publique France, French
acronym SPF) and the Sentinel Network [6], the varicella annual incidence rate in France in
2019 was 822 cases per 100,000 inhabitants, or approximately 540,000 cases per year. Similar
trends were observed in 2017 and 2018, with 557,000 cases and 561,000 cases per year,
respectively. Stable rates were thus observed over time, except in 2020 with only 230,000
total cases reported (about 40% lower than usual) [6]. These figures confirm data obtained
from outpatient pediatricians via the French Pediatric and Ambulatory Research in Infectious
diseases (PARI) network, which observed a decrease in varicella visits in 2020 [7]. Personal
NPIs and population containment are clearly involved in this decrease. Due to the unavoidable
nature of varicella, young children who should have contracted chickenpox in 2020 will be
added to the susceptible population and will possibly contribute to a higher incidence in the
coming years. In addition, the population that has not had chickenpox in 2020 will have "aged"
and this may lead to a greater number of severe and complicated cases. In France, vaccination
against varicella is targeted at specific populations at risk of severe forms. However, since
varicella vaccination offers protection similar to that conferred by the natural infection [8] and
protects against herpes zoster, this vaccination policy could be reconsidered in this new
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context to avoid an epidemic rebound by implementing broader vaccination guidelines
already adopted in many high-income countries [9].
I.A.2. Respiratory syncytial virus infections
Illnesses due to RSV range from benign upper respiratory tract infections including ear
infections, to potentially serious lower respiratory tract infections (severe bronchiolitis and
pneumonia [10]). In 2015, RSV was responsible for 33.1 million episodes of acute lower
respiratory tract infections in children under 5 years of age worldwide [11]. RSV infections in
young children are a major cause of hospitalization and mortality in low-income countries and
a major cause of hospitalization in high-income countries. Bronchiolitis is the most
characteristic clinical syndrome, although not the most common. It is the best marker of RSV
epidemics. It affects children under 2 years of age during seasonal winter epidemics in
northern countries and is the leading cause of hospitalization among RSV-related illnesses
[1214]. All 2-year-olds have been infected at least once [5]. Transmission of RSV occurs by
large droplets and contact with contaminated surfaces and is thought to occur more
frequently among children in day-care centers and schools [16]. RSV and SARS-CoV-2 have
similar baseline R0 reproduction rates (approximately 3) [17,18]. As for the reservoir and
transmission of RSV, the role of adults and older children during winter epidemics is still not
clearly defined [10]. However, bronchiolitis in infants aged below 3 months of age, which
generates numerous hospitalizations for acute respiratory failure each winter and overloads
pediatric services, is mainly the result of intrafamilial transmission. It often involves parents
who can also be infected during winter by RSV. The experience of the great transport strike of
1995, which abruptly interrupted the epidemic curve of bronchiolitis in the pediatric
emergency rooms of the Paris area, was an illustration of this pattern [19].
In the first six months of the COVID-19 pandemic, initial epidemiological data from the
Southern Hemisphere and particularly from Australia, showed the virtual absence of RSV
infection and influenza epidemics, more than three months after the usual start of annual
epidemics [20]. In contrast, Australia reported as early as October 2020 (corresponding to
mid-spring in the Southern Hemisphere) a larger RSV epidemic [21] than in previous seasons,
without any influenza virus epidemic.
In France, during the 2020-2021 winter season bronchiolitis was characterized by an epidemic
cycle that occurred three months later than the second epidemic peak of COVID-19 and was
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strongly reduced in intensity (more than a third) compared to the previous years, both in
ambulatory and hospital settings.
The absence of strong RSV epidemic will have increased the proportion of RSV-susceptible
children that may increase their risk of RSV infection over time. In the absence of an RSV
vaccine, partial and transient immunity is naturally and spontaneously achieved each year by
two mechanisms: infection or transplacental transfer of maternal RSV antibodies.
Due to the decreased spread of RSV this year as a result of anti-COVID-19 measures, the
natural protection of the population against RSV at the end of winter will be lower than usual,
raising fears of a more important RSV epidemic in the future [4]. The evolution of NPIs, and
particularly their lifting, will have major effect on the incidence. Continued surveillance of RSV
infections will be necessary to detect early epidemic in order to adapt the prophylaxis of young
infants at risk (especially very premature infants) with palivizumab and to prepare the
healthcare system.
I.A.3. Rotavirus
The incidence of acute diarrhea illnesses followed the same downward trend as other viral
infections since the beginning of the SARS-CoV-2 epidemic. Even if the sentinel network notes
a slight increase in the number of consultations for acute diarrhea in recent weeks, the rate
remains much lower than the figures usually observed at this period. The incidence rate of
acute diarrhea cases seen by family physicians was 367 cases per 100,000 inhabitants [22]
during the second week of January 2020, before the beginning of the epidemic (similar rate
to those of previous years), while it is only 98 cases per 100,000 inhabitants in 2021. Data
provided by the PARI network confirm this decrease [7]. Rotavirus is the main pathogen
responsible for acute diarrhea in children because of its frequency but also because of its
potential severity in infants [23]. Indeed, rotavirus is frequently responsible for acute
gastroenteritis with severe dehydration and usually causes more than 200,000 child deaths
per year worldwide. Most of these deaths mainly occur in developing countries, but it should
be noted that the number of deaths in France is significant, with an estimated 20 cases per
year [23,24].
It is almost unavoidable to have had rotavirus infection before the age of 3, i.e. the age group
in which most severe forms are reported [25]. Reinfections are also common but associated
with milder forms. Rotavirus vaccination prevents severe forms and also reduces the overall
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number of cases in countries where the vaccine is widely administered. Similar to varicella,
we can fear an epidemic rebound after the current pandemic.
I.A.4. Measles
As in most countries, France has seen a rapid decline in the number of measles cases since
April 2020, whereas 2019 was an epidemic year [26]. This requires optimal measles, mumps,
and rubella (MMR) vaccination coverage if we wish to avoid significant epidemic rebounds in
the coming years. Coverage was however not optimal in 2020.
I.A.5. Other viruses
The situations described above represent a significant proportion of pediatric consultations
and seasonal epidemics, but the decrease in various viral infections is observed with many
other viruses.
Seasonal influenza usually occurs from the end of December onwards. No such epidemic has
been observed so far this year [27]. With an R0 much lower than that of SARS-CoV-2 and an
identical mode of transmission, the absence of influenza epidemic was expected as long as
NPIs were maintained. However, future epidemics are less predictable because many other
factors could play a role: virus variability over time, role of population migration, and annual
vaccination of at-risk subjects with a vaccine which matching patterns to the circulating viruses
and related effectiveness vary every year. The potential role of animal influenza viruses is also
at stake.
Enteroviruses are no exception: reports of enterovirus infections by pediatric emergency
rooms and by the pediatrician network also decreased [7,28]. These viruses are responsible
for numerous cases of pharyngeal, cutaneous, and digestive infections in infants and children,
which are generally benign. More severe forms may however be observed, such as sepsis-like
syndrome in newborns and meningitis, leading to frequent hospitalizations of younger
children.
I.B. Bacterial diseases
While the rate of visits for ambulatory pediatric infectious diseases has decreased, the same
is true for invasive infections with encapsulated bacterial species such as S. pneumoniae,
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N. meningitidis and H. influenzae b. A significant decrease in the number of lower and upper
respiratory tract infections, but also bacteremia and meningitis, was observed in 2020-2021.
I.B.1. Streptococcus pneumoniae
This was confirmed by a large study conducted between January 2018 and May 2020 across
26 countries in six continents [3]. The authors compared the rates of invasive pneumococcal
disease in 2020 vs 2018-2019, week by week. The same conclusion was reached in all countries:
significant decrease in invasive pneumococcal diseases, regardless of NPIs (school closures,
telecommuting, lockdown, etc.). The PARI network also reported a 50% decrease in the
number of visits for acute otitis media or pneumonia as compared to previous years [7]. This
result was expected as Streptococcus pneumoniae is mainly carried in the nasopharyngeal and
oropharyngeal microbiota of children aged under 6 years. Transmission occurs by droplets and
is either leading to healthy carriage or less frequently to infection. No study investigated the
impact of the pandemic on pneumococcal carriage, but one can hypothesize that the
decreased incidence of invasive pneumococcal disease may be related to an overall decrease
in carriage. Moreover, pediatric pneumococcal carriage and infection are favored by viral
infections, but the incidence of such infections has also decreased. Since the 1980s, following
the work of Gray [29,30], it has been known that all infants will be colonized by various
serotypes of Streptococcus pneumoniae in the first years of life. Most of them progressively
develop mucosal and systemic immunity against these various serotypes without showing
clinical signs of infection, underlining that asymptomatic or paucisymptomatic carriage can
induce protective effect. The decreased circulation of pneumococcal strains due to NPIs will
probably be associated with a higher proportion of children susceptible to these strains.
Although vaccination with conjugate vaccines significantly reduced the risk of vaccine
serotype pneumococcal infections, the risk of non-vaccine serotype carriage has increased.
However, despite the protective role of some serotypes able to limit colonization by more
virulent serotypes, serotypes with high disease potential (24F, 12F, 8, etc.) which were
predominant before the pandemic are likely to remain so after the pandemic [31].
This period of low circulation or low carriage could be followed by an increase in invasive
infections if we assume that more children or adolescents are immunologically "naive" to
pneumococcal serotypes with high invasive potential and not covered by vaccines. The
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availability of new generations of conjugate vaccines, covering more serotypes, may limit the
extent of such rebound effects.
I.B.2. Neisseria meningitidis
The number of pediatric serogroup C invasive meningococcal disease (CIMD) cases has
declined since 2017, driven successively by the implementation of the 5-month vaccination
dose in 2017 and the extension of mandatory vaccines in 2018, while IMDs due to other
serogroups remained stable (serogroups B and Y) or increased (serogroup W) throughout
2019 [32]. The first lockdown was associated with a significantly lower number of IMD reports
compared to the corresponding periods in 2018 and 2019 both in France and in 25 other
countries worldwide. This trend was observed regardless of the stringency of NPIs taken by
countries [3]. Moreover, in France, this decrease during the lockdown period mainly involved
isolates of hyperinvasive genotypes, regardless of the serogroup, whereas the circulation of
less invasive isolates did not vary.
Clinical presentations of these invasive infections were also found to have changed during the
lockdown period with an increase in respiratory forms, a higher proportion of elderly people
affected, and involvement of unusual isolates. This suggests that these isolates, although less
virulent, could be carried for a longer period [33]. The average duration of asymptomatic
carriage can be as long as four months [34]. Hyperinvasive isolates have a high
acquisition/transmission/attack rate compared to carriage isolates (less invasive but carried
for a longer time) [35]. In the short term, hyperinvasive isolates would therefore be more
impacted by anti-COVID-19 measures. However, an impact on asymptomatic meningococcal
carriage could be observed if these measures were to be continued. Asymptomatic carriage
of N. meningitidis or closely related species such as Neisseria lactamica contributes to the
development of herd immunity to Neisseria meningitidis in the general population [34]. This
potential decline in natural immunity could be exacerbated by declining vaccination coverage
as observed in France and in the United-Kingdom [36] with an uncontrolled delay in
vaccination in 2020 that will increase in 2021. These changes in the circulation of isolates, the
reduced carriage, and the delay in vaccination may thus be a sign of a decline in meningococcal
herd immunity and an increase in the number of individuals susceptible to meningococcal
infections. This raises concerns about a rebound effect in the incidence of IMDs. Preventive
action should therefore be prepared immediately. A plan to boost vaccination is necessary for
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meningococcal C conjugate vaccination (infant vaccination but also catch-up vaccination in
children, adolescents, and young adults) and a vaccination strategy extended to other
serogroups (A, Y, and W or even B) could be considered.
I.B.3. Pertussis
Pertussis is also strongly impacted by the SARS-CoV-2 epidemic. According to the unpublished
data of the PARI and ACTIV networks (pertussis cases diagnosed in outpatient settings by
pediatricians) and the PCR results from the main laboratory in France performing pertussis a
90% drop in the number of cases was observed [7]. This is once again probably due to the
decreased circulation of B. pertussis due to anti-COVID-19 measures. However, even if the
incidence of the disease strongly decreased since the introduction of booster vaccines, the
bacterium is still circulating especially in adults and the elderly as shown by sero-
epidemiological studies conducted in various countries. This may be due to non-optimal
vaccination coverage in these populations.
Unlike other infections, pertussis is not an unavoidable childhood disease [37], and the
rebound effect associated with an "immunity debt" built up in 2020 will probably not be
observed in this disease if vaccination coverage remains high. However, delays in vaccination
were observed in France among infants since the beginning of the pandemic. Such delays are
particularly detrimental to children under 3 months of age, in whom pertussis can have a very
serious course (malignant pertussis). To mitigate this risk, vaccination of mothers against
pertussis during pregnancy should be implemented in France as soon as possible, especially
as its effectiveness has been widely demonstrated in several European, North and South
American countries and in Australia [38,39]. In addition, delays in vaccination are also
observed with the booster shots administered at the age of 6, 11-13, and 25 years which
coverage rates must absolutely be increased. Finally, the cocooning strategy must be
reinforced because grandparents can transmit pertussis to non-immunized adults and young
infants [40]. Acellular pertussis vaccines are very effective against the disease but seem to
have little effect on carriage and induce immunity that rapidly declines over time [41].
Vaccination recommendations should be strictly followed and could even be strengthened by
introducing a pertussis booster after the age of 25 years to increase herd immunity.
II. Other collateral effects of the pandemic
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II. A. Impact on immunization programs and vaccine delays
Prior to the pandemic, infant and young children vaccination coverage rates were usually good
in many countries. In France, a significant improvement was reported over the last years,
because of the extension of mandatory vaccination implemented in January 2018 [42].
Vaccination coverage (at least three doses by 15 months) was over 94% for the hexavalent
vaccine and 93% for the 13-valent pneumococcal vaccine. Vaccination coverage figures for
hepatitis B (three doses by 15 months), MMR (one dose at 15 months), and meningococcal C
(two doses by 15 months) were admittedly lower and insufficient, but a significant increase in
2017 was observed compared with 2019. However, vaccination coverage for booster shots,
particularly DTPaP (diphtheria, tetanus, poliomyelitis, and acellular pertussis) at 6 and 11 years
of age, and for HPV vaccination remained insufficient. This insufficiency increases with
increasing age (population of 25 years and older), with less vaccinations performed and poor
compliance with the recommendations of the French High Council for Public Health (French
acronym HCSP) (pertussis not performed).
The COVID-19 pandemic had an impact on all vaccination coverage rates [43] as they all
decreased, sometimes even sharply, particularly during the lockdown periods and were not
fully restored afterwards [44]. Indeed, during the first lockdown implemented in March 2020,
a strong decrease in physician visits was observed, including well-baby visits. The health crisis
impacted all consultations for DTPaP booster vaccination, including pediatric appointments at
6 and 11-13 years.
Vaccine delivery has also drastically been reduced since 2020 despite improvement in August
2020, and the overall downward trend continued into early 2021. According to the data from
Epiphare [44], for an annual birth cohort of approximatively 780,000, the number of missed
vaccinations since March 2020 is:
- 70,000 for hexavalent (Diphtheria-Tetanus, inactivated poliomyelitis, Pertussis, Haemophilus
B and hepatitis B) vaccines;
- 150,000 for Measle-Mumps-Rubella vaccines;
- 230,000 for papillomavirus vaccines;
- 720,000 children, adolescents, and adults not vaccinated with a tetanus containing vaccine.
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Compared to many high-income countries, France has a less extended childhood vaccination
scope, i.e., lacking rotavirus, varicella, Neisseria meningitidis serogroup B and Neisseria
meningitidis serogroup ACYW vaccination program (Table 1).
II.B. Impact of the immunity debt on trained immunity
Children seem to be less often infected with SARS-CoV-2 than adults and present with less
severe forms than adults [45]. Various hypotheses have been raised to explain this relative
resistance of children to SARS-CoV-2: less ACE2 receptors, frequency of infections with
common coronaviruses likely to induce cross immunity, role of trained innate immunity [46].
Indeed, one of the first lines of natural defense against pathogens is the innate immunity
which role is to produce an immediate, rapid but non-specific response to an infectious
aggression (phagocytosis, production of cytokines, etc.) and which effectiveness has limits.
The immune system also develops an adaptive immune response, specific to the pathogen,
allowing more effective protection during subsequent exposure to the same pathogen thanks
to the development of an immune memory. In recent years, several studies suggested that
frequent stimulations and "training" of innate immunity would increase its effectiveness [47].
This stimulation by exposure to various pathogens is undoubtedly more frequent in children
than in adults. The concept of trained immunity corresponds to a kind of long-term functional
reprogramming of innate immune cells, stimulated by pathogens and which would lead to a
reinforced response during subsequent exposures. This process would have great advantages
for host defense. Thus, this trained immunity would be established in children particularly
exposed to viral infections in the first years of life and would be more effective in them than
later in adulthood. The probable role of live vaccines, administered in childhood, on this
trained immunity is being studied. The reduction of infectious contacts secondary to hygiene
measures imposed by the pandemic may have led to a decreased immune training in children
and possibly to a greater susceptibility to infections in children.
II.C The hygienist theory
The hygienist theory is based on observations made over the past decades: the decreased
incidence of infections in Western countries is temporally associated with an increasing
incidence of autoimmune and allergic diseases [48]. Studies also suggested the involvement
of the microbiota, particularly the intestinal microbiota, in the increased incidence of these
allergic and secondary autoimmune diseases [49]. In the era of lockdowns and NPIs, it seems
Page 14 of 18
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14
legitimate to hypothesize and assess the impact prolonged adoption of NPIs and reduction of
infectious diseases as a whole may have on the imbalance of the intestinal microbiota and the
related occurrence of allergic and autoimmune pathologies.
Conclusions
Low viral and bacterial exposures due to NPIs imposed by the COVID-19 pandemic raise
concerns as we may witness strong pediatric epidemic rebounds once personal protection
measures are lifted. In addition, the decrease in vaccination coverage and the potential
increased number of cases of vaccine preventable diseases are of concern. This should lead to
the implementation of reinforced catch-up vaccination programs. The French vaccination
schedule does not include vaccines against rotavirus, varicella, and Neisseria meningitidis
serogroup B and ACYW; France could thus be more vulnerable to some of these epidemic
rebounds. This should lead to advocacy for the expansion of the French vaccination schedule.
Finally, for diseases for which there is no vaccine, rapid screening, timely re-enforcement of
hygiene measures, and adaptation of healthcare systems should be implemented.
Contribution of authors
RC, MA, MKT, EV, FA, CL, AR, NO, NG, and EG drafted the article. All authors revised and
approved the article.
Page 15 of 18
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15
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Table 1. Additional vaccines included in childhood vaccine schedules in high-income countries
Rotavirus
Neisseria meningitidis
serogroup ACYW
Varicella
United-
States
+
+
+
Canada
+
+
+
United-
Kingdom
+
+
-
Ireland
+
+
-
Belgium
+
+
Netherland
+
+
Switzerland
+
Italy*
+
+
+
Spain
+
+
Portugal
+
+
Israel
+
+
* According to the region these vaccines could become mandatory or recommended and
reimbursed
** According to the region
... Over the last 3 years, the nightmarish COVID-19 pandemic imposed unprecedented nonpharmaceutical interventions (NPIs) which impacted the epidemiology of many other pediatric infectious diseases [1,2]. Prolonged reduction of exposure to many viruses and bacteria resulted in a lack of immune stimulation against varied community-acquired pathogens, leading to expansion of the "naive" population to these pathogens and to the decline of herd immunity, making children more vulnerable to these infections [3]. In this context and in this journal, a year and a half ago our group put forward the concept of "immune debt" [3]. ...
... Prolonged reduction of exposure to many viruses and bacteria resulted in a lack of immune stimulation against varied community-acquired pathogens, leading to expansion of the "naive" population to these pathogens and to the decline of herd immunity, making children more vulnerable to these infections [3]. In this context and in this journal, a year and a half ago our group put forward the concept of "immune debt" [3]. Briefly, after barrier measures were lifted, we raised concerns about the epidemiological rebound of many infectious diseases of varying severity and the occurrence of unpredictable epidemics throughout one year [3,4]. ...
... In this context and in this journal, a year and a half ago our group put forward the concept of "immune debt" [3]. Briefly, after barrier measures were lifted, we raised concerns about the epidemiological rebound of many infectious diseases of varying severity and the occurrence of unpredictable epidemics throughout one year [3,4]. Worldwide, many researchers published articles concurring with our concept of "immunity debt", which is also called "immunity gap" [5][6][7][8]. ...
... Furthermore, COVID-19 related global lockdowns had significantly reduced social interactions and confinements in small spaces (classrooms), whilst accelerating the adoption of non-pharmaceutical interventions (NPIs) like hand hygiene, use of face mask and other. These positive measures helped in keeping the load of many viral and bacterial paediatric infections low during the pandemic [22,23]. However, on the other side, it led to reduced immune stimulation (due to reduced transmission and delayed contact with microbial agents) and lower vaccine uptake, thereby causing a so-called "immune debt" [23]. ...
... These positive measures helped in keeping the load of many viral and bacterial paediatric infections low during the pandemic [22,23]. However, on the other side, it led to reduced immune stimulation (due to reduced transmission and delayed contact with microbial agents) and lower vaccine uptake, thereby causing a so-called "immune debt" [23]. In fact, it has been argued that longer the periods of lockdowns, the greater the risk of future epidemics (rebound effect) due to growing proportion of susceptible individuals and declining herd immunity [23]. ...
... However, on the other side, it led to reduced immune stimulation (due to reduced transmission and delayed contact with microbial agents) and lower vaccine uptake, thereby causing a so-called "immune debt" [23]. In fact, it has been argued that longer the periods of lockdowns, the greater the risk of future epidemics (rebound effect) due to growing proportion of susceptible individuals and declining herd immunity [23]. Further guidelines for schools is available from https://www.gov.uk/government/ ...
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... Furthermore, increased hygienic measures during the pandemic may have decreased children's immune training, which made them more susceptible to infection 24 . Immunity debt implies the lack of protective immunity caused by prolonged low exposure to a specific pathogen. ...
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Background – The incidence of pediatric asthma exacerbations during the COVID-19 pandemic has been evaluated; however, the incidence of severe acute asthma (SAA) requiring a Pediatric Intensive Care Unit (PICU) admission is unknown. Furthermore, we examined several factors which might influence this incidence, such as environmental triggers or changes in COVID-19 lockdown regulations. Methods – In this single-center, retrospective cohort study running from 2018 to 2021, all PICU admissions for SAA of children above two years of age at a tertiary hospital in the Netherlands were included. Information on potential asthma triggers during the pandemic, including viral infections, concentrations of ambient fine particulate matter (PM2.5) and pollen index were evaluated. Results – In total, 168 children were included in this study. While we observed a decrease in PICU admissions for SAA during lockdown periods, there was an increase in the admission rates in the periods without a lockdown, with the highest peak from August to November of 2021. This peak in the fall of 2021 did not align with pollen or ambient PM2.5 concentrations (r =-0.04 for pollen and r =0.23 for PM2.5). Discussion – COVID-19 lockdowns influenced the admission rates for SAA at the PICU both during and after the lockdowns in the Netherlands. We hypothesize that an increase in viral infections after lockdown periods was the reason for the altered incidence of SAA at the PICU in late 2021, rather than air pollution and pollen concentrations.
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Public health measures targeting coronavirus disease 2019 have potential to impact transmission of other respiratory viruses. We found 98.0% and 99.4% reductions in respiratory syncytial virus and influenza detections, respectively, in Western Australian children through winter 2020 despite schools reopening. Border closures have likely been important in limiting external introductions. © 2020 The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]
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