INTRODUCTION
The COVID-19 pandemic has been a global phenomenon since the later part
of 2019 and will likely continue to represent a serious health crisis
well into 2021. Early experience with the disease, particularly in China
created perceptions about the disease regarding its infectivity,
transmission, lethality and disease progression in general which created
an initial benchmark for the development of treatment strategies that
include an array of modalities dominated by repurposed drugs and
vaccines. The availability of these agents was created to a large extent
by previous efforts to combat the Ebola virus and other infectious
diseases. While clinical trials are ongoing, the virus continues to
spread and likely mutates as it touches every corner of the world
challenging our initial perception of its progression, infectivity and
transmission as well as long term effects, relevant co-morbidities and
other risk factors. Both pregnant women and children represent typical
vulnerable populations for drug and vaccine therapy and are likewise
commonly excluded from early clinical trials. Nonetheless, they are not
immune to the disease and reflect an important subpopulation that
clinical pharmacologists and the entire medical community are called
upon to advise regarding the treatment strategy, choice of medication
and dosing of potentially life-saving agents.
Data are sparse on the effects of medication use during pregnancy.
Despite the fact that half of the world’s population is female with the
majority of women becoming pregnant at some point and many of those
women taking some kind of medication during their pregnancy, women are
still typically prescribed formulaic therapy, using doses extrapolated
from nonpregnant women, men, or pregnant animals. Children (newborns
through adolescents) do not fare much better with extrapolation
strategies anchoring limited investigation.1
Existing COVID-19 treatment options for both pediatric patients and
infected pregnant women are mostly supportive in nature and focus on
sufficient fluid and calorie intake and additional oxygen
supplementation. The intention in these situations is typically focused
on preventing ARDS, organ failure and secondary nosocomial infections.
The only treatment recommendation for children, published by the
Zhejiang University School of Medicine, suggests the use of nebulized
interferon alpha-2b and oral lopinavir/ritonavir together with
corticosteroids for complications (ARDS, encephalitis, hemophagocytic
syndrome or septic shock) and intravenous immunoglobulin for severe
cases.2 In a broader context, repurposing strategies
and new drug development in general target the three key stages of
infection: preventing the virus entering our cells in the first place,
stopping it replicating if it gets inside the cells, and reducing the
damage that occurs in tissues; in the case of COVID-19, the lungs and
heart.
The objective of this work was to assess the vulnerabilities of
pediatric patients and pregnant women to potential therapeutic
strategies under consideration to treat the COVID-19 pandemic and the
SARS-CoV-2 virus; both drug and vaccine candidates were considered and
the effort was focused primarily on repurposed drug candidates and
vaccines previously screened for other pathogens (e.g. Ebola). A
systematic review of the current COVID-19 disease etiology in these
populations along with a review of available clinical experience with
potential drug and vaccine candidates in these populations was
undertaken with the intention to summarize the available information and
assess potential risk factors which may pose an additional safety
concern or suggest dose modification in these populations.
METHODS:
The conduct of COVID-19 clinical vaccine and drug trials was determined
through systematic searching of the Clinical Trials.gov website.
Similarly, each trial was reviewed for the targeting or inclusion of
pediatric patients or pregnant women as well as any criteria describing
risk to these populations or special precautions (e.g., breast feeding,
contraception, etc). The search for current, 2019-2020, peer-reviewed
articles via the National Library of Medicine’s PubMed site and included
Academic OneFile, JSTOR, Sage Journals, and related databases. Google
Scholar was also utilized to locate open access articles. Some of the
key search terms used to locate articles specific to this review
included: “pediatrics” , “pregnancy” ,
“vaccine”, and “drug trials” . All terms in each
database combined with Boolean operators (AND, OR and/or NOT). Guidance
documents were accessed from FDA and EMA websites and pregnancy
categories and drug labels of repurposed drugs were accessed directly
from the sponsor’s website or other publicly available sites. Identified
clinical trials for drug, drug combinations and vaccine investigations
were reviewed for their inclusion (or not) of pediatric patients and
pregnant women.
DISEASE MANIFESTATION
The SARS-CoV-2 virus enters the host cell via the angiotensin-converting
enzyme 2 (ACE2) receptor, to which it attaches via the spike (S) protein
on the virus envelope. Another host protein called transmembrane protein
serine protease TMPRSS2 also plays a vital role in processing the S
protein and receptor. This is necessary for further interaction of the S
protein and ACE2 receptor leading to infection.3,4Enhanced entry correlated with TMPRSS2-mediated proteolysis of both S
and ACE2. These findings indicate that a cell surface complex comprising
a primary receptor and a separate endoprotease operates as a portal for
activation of virus cell entry. This mechanism is relevant for enveloped
coronaviruses (CoVs) in general as they mediate cell entry by connecting
viruses to plasma membrane receptors and by catalyzing subsequent
virus-cell membrane fusions.
The incubation period for COVID-19 is thought to extend to 14 days, with
a median time of 4-5 days from exposure to symptoms
onset.5 One study reported that 97.5% of persons with
COVID-19 who develop symptoms do so within 11.5 days of SARS-CoV-2
infection.6 The signs and symptoms of COVID-19 present
at illness onset vary, but over the course of the disease, most persons
with COVID-19 will experience the following: fever (83–99%), cough
(59–82%), fatigue (44–70%), anorexia (40–84%), shortness of breath
(31–40%), sputum production (28–33%), myalgias (11–35%). Atypical
presentations have been described, and older adults and persons with
medical comorbidities may have delayed presentation of fever and
respiratory symptoms.7-11 Some persons with COVID-19
have experienced gastrointestinal symptoms such as diarrhea and nausea
prior to developing fever and lower respiratory tract signs and
symptoms.11,12 Anosmia or ageusia preceding the onset
of respiratory symptoms has been anecdotally reported, but more
information is needed to understand its role in identifying COVID-19.
Several studies have reported that the signs and symptoms of COVID-19 in
children are similar to adults though the disease course is usually
milder compared to adults13,14 but this of course is a
generalization based on limited data. Table 1 provides a comparison of
COVID-19 disease manifestation between children and adults.
Fu et. al.15 retrospectively analyzed epidemiological
characteristics of 2143 children affected by SARS-CoV-2 infection in
China, supporting the evidence that children are as susceptible as
adults to infection. They found an elevated vulnerability to SARS-CoV-2
among infants, with a proportion of severe and critical cases of 10.6%
in this age group.15 However, most severe and critical
cases in the study were not SARS-CoV-2 confirmed, questioning whether
other untested pathogens could have been responsible for these clinical
events.16 Figure 1 shows the COVID-19 disease
trajectory indexed with time-based events during pregnancy and childhood
development that present concerns for pharmacotherapy
intervention.17,18
PHYSIOLOGIC DYNAMICS WHICH CONVEY DOSING CHALLENGES
During pregnancy, the pregnant mother undergoes significant anatomical
and physiological changes to nurture and accommodate the developing
fetus. These changes begin after conception and affect every organ
system in the body. For most women experiencing an uncomplicated
pregnancy, these changes resolve after pregnancy with minimal residual
effects19. Pregnancy is a complex state where changes
in maternal physiology have evolved to favor the development and growth
of the placenta and the fetus. Likewise, pregnancy represents a moving
target with respect to optimal pharmacotherapy. Variations in physiology
have been shown to alter the pharmacokinetics or pharmacodynamics that
determines drug dosing and effect. It follows that detailed
pharmacologic information is required to adjust therapeutic treatment
strategies during pregnancy. The impact of pregnancy on the various
underlying pharmacokinetic processes and physiologic conditions that
change during pregnancy (e.g., pregnancy-induced enzyme-specific
changes, transporter differences, etc) has been previously
reviewed20 but much of the actual risk towards
prescribing drugs to pregnant women revolves around the fact that much
of the dosing information available is based on men and nonpregnant
women and is hence extrapolated.
Pregnancy-induced maternal physiological changes may affect
gastrointestinal function and hence drug absorption rates. Ventilatory
changes may influence the pulmonary absorption of inhaled drugs. As the
glomerular filtration rate usually increases during pregnancy, renal
drug elimination is generally enhanced, whereas hepatic drug metabolism
may increase, decrease, or remain unchanged. A mean increase of 8 L in
total body water alters drug distribution and results in decreased peak
serum concentrations of many drugs. Decreased steady-state
concentrations have been documented for many agents because of their
increased clearance. Pregnancy-related hypoalbuminemia, leading to
decreased protein binding, results in increased free drug fraction.
However, as more free drug is available for either hepatic
biotransformation or renal excretion, the overall effect is an unaltered
free drug concentration. Since the free drug concentration is
responsible for drug effects, the above-mentioned changes especially in
light of the compensation observed are probably of no clinical
relevance. The placental and fetal capacity to metabolize drugs together
with physiological factors, such as differences acid-base equilibrium of
the mother versus the fetus, determine the fetal exposure to the drugs
taken by the mother. As most drugs are excreted into the milk by passive
diffusion, the drug concentration in milk is directly proportional to
the corresponding concentration in maternal plasma. The milk to plasma
(M:P) ratio, which compares milk with maternal plasma drug
concentrations, serves as an index of the extent of drug excretion in
the milk. For most drugs, the amount ingested by the infant rarely
attains therapeutic levels. Many of these factors are routinely
determined during early phase drug development as part of a sponsor’s
IND submission and this information is likely available for repurposed
drug candidates under consideration to treat
SARS-CoV-2.21
While the relationship between developing pediatric physiology and
pharmacokinetic attributes is generally at least qualitatively
appreciated, far less emphasis has been placed on the relationships
between developmental considerations and pharmacologic pathways. As
these represent the target mechanisms of action and/or the off-target
effects that govern toxicity, they are often critical in the assessment
of the pediatric therapeutic window. These relationships likewise have
been absent in the discussion of pediatric development plans and
decision trees used to define regulatory expectations for such
plans.22
Factors such as changes in body composition, total body water, protein
binding, cytochrome P450 ontogeny, gastro-intestinal motility and pH,
and organ (e.g., renal and hepatic) function all of which can produce
significant changes in absorption, distribution, metabolism, and
elimination throughout childhood. Human milk is a suspension of protein
and fat globules in a carbohydrate-based suspension. The mechanisms by
which medications are transferred into breastmilk are no different than
those governing passage into any other maternal body fluid or organ
system. Most drugs are transferred across membranes by passive
diffusion, reaching a concentration equilibrium with the concentration
in the blood. Other factors affecting the degree of transfer into a
given fluid or tissue include the lipophilicity of the compound, the
degree of ionization, and the extent of protein binding. Medications
with a low molecular weight that are nonionized and lipophilic are the
most likely to be transferred into breastmilk. In addition to passive
diffusion, medications also may be transferred into breastmilk
incorporated within fat globules or bound to proteins, primarily case in
and lactalbumin. Highly protein-bound drugs, though, are unlikely to
cross extensively into breastmilk since these drugs bind preferentially
to serum albumin. By overlaying the PK and PD attributes of target drug
molecules, we can get a sense of the susceptibility for the underlying
PK (absorption, distribution, metabolism and elimination) and PD
(receptor affinities, dissociation, enzyme kinetics, signal
transduction, cascade events, etc) processes to be affected by changes
in the aforementioned physiologic factors. Likewise, knowledge of
pediatric clinical pharmacology is essential to the design and conduct
of informative pediatric trials. More than ever, pharmaceutical sponsors
are encouraged to plan for the pediatric investigation as an essential
part of their clinical development plans. For older drugs on the market,
NIH and FDA collectively administrate the appropriation of funds that
support pediatric research for off-patent drugs through the Best
Pharmaceuticals for Children Act (BPCA).23
Tables 2 and 3 summarize the physiological and pharmacokinetic factors
respectively which contribute to the dynamic changes that occur in both
pregnancy and pediatric subpopulations that make both groups vulnerable
to pharmacotherapy especially in the absence of targeted investigation
(i.e., extrapolations form mainstream patient trials from which they are
typically excluded).
VACCINES
With respect to the vaccines under development to treat COVID-19,
efforts ramped up quickly while still early in pandemic onset. As of
April 2020, there were 115 vaccine candidates in some stage of
development.24 There was a broad array of strategies
employed; some of these represented next-generation technology platforms
and others had been repurposed from efforts to develop an Ebola
vaccine.25 In any case, multiple stakeholders
including the vaccine development industry, the Coalition for Epidemic
Preparedness Innovations (CEPI) and the World Health Organization (WHO)
have joined forces to quickly advance efforts into clinical stage
testing all while informing the global regulatory community and securing
their “buy-in” to the accelerated pace of evaluation and testing. As
with drug development, there is some hesitation to expose children and
pregnant women in early phase testing particularly when the viability of
these candidates is unknown. The most advanced of these candidates have
been assessed herein for their intentions and any unusual risk factors
that these candidates may possess. In addition to the adenovirus type-5
(Ad5) vectored COVID-19 vaccine, seven candidate COVID-19 vaccines are
in ongoing clinical trials, including Moderna’s mRNA COVID-19 vaccine,
Inovio Pharmaceuticals’ DNA vaccine, Sinovac, Wuhan and Beijing
Institute of Biological Products’ inactive COVID-19 vaccines, University
of Oxford’s chimpanzee adenovirus-vectored vaccine, and BioNTech’s mRNA
COVID-19 vaccine. A more current and accurate view of the landscape of
COVID 19 candidate vaccines can be found at the World Health
Organization’s website.26
MECHANISTIC ASSESSMENT OF RISK IN SPECIAL POPULATIONS
Historically, the interests of pregnant women have not adequately
featured in global responses to outbreaks and epidemics. Funders have
not asked if the vaccine candidates they are investing in are suitable
for pregnant women, and pregnant women have not been included in vaccine
trials. The absence of data about the effects of vaccines during
pregnancy has in turn resulted in delays or outright denials of access
to lifesaving vaccines, as evident in recent responses to Ebola
outbreaks.27 Vaccine risk in pregnant women is
generally considered low, especially if the vaccine is not a live or
attenuated virus. Most risk-assessment models are for preterm birth,
perinatal morbidity and mortality, Cesarean delivery, or vaginal birth
after Cesarean or uterine rupture. No risk-assessment models, or tools,
specifically address the risk of maternal morbidity and mortality
however and there is no consensus on how to judge pharmacotherapy risk
either. The U. S. Food and Drug Administration (FDA)’s list of
Pharmaceutical Pregnancy Categories help doctors (and their patients)
know the prenatal safety of approved medications. The categories are A,
B, C, D, and X. Drugs within Category A have been found to be safe for
use in pregnant women, whereas drugs within Category X have been found
to be harmful to fetuses and should not be used by pregnant
women.28 When available, these have been listed in
Table 4 (discussed below).
Regarding the risk of pharmacotherapy to children, most medications are
formulated and packaged for adults, which requires manipulation of the
dosage form to administer the precise dose to the child. This creates
uncertainty around the diagnosis and the assignment of pharmacotherapy.
Additionally, pediatric patients often cannot communicate effectively to
providers and/or caregivers any adverse effects caused by medications
making risk difficult to assess. Likewise, in the fetus and newborn
caregivers are also concerned with maternal-fetal transfer. In most
cases, placental transfer is only estimated based on preclinical
toxicity experiments by the sponsor with guidance provided in package
insert. Despite the dramatic increase in the percentage of women
choosing to breastfeed, knowledge of the safety of most medications
remains limited. Research into the quantity of drug transferred into
milk is complex and provides only a limited degree of certainty on the
safety of medication use.
When we consider the risks associated with vaccine administration it
should be broadly appreciated that under most situations the risk of
harm is greater from not vaccinating a child or pregnant women. In
August 2011, the Institute of Medicine (IOM) released a report that
examined eight childhood vaccines and potential side
effects.29 It found that vaccines are largely safe and
that side effects are usually very rare and minor. Nonetheless, there
are considerations for both populations that need to be addressed. The
overwhelming medical evidence finds that most vaccine side effects among
newborns and young children are mild—swelling, redness and a small,
hard lump at the site of the injection—and typically pass within a
couple of days. A far less common but serious vaccine side effect,
occurring in fewer than one in a million cases, is an immediate allergic
reaction that can be treated with common medications to ease itching or
swelling or, in more serious cases, by administering epinephrine.
Rarely, with certain vaccinations there can be other problems. After
receiving the first shot of the measles-mumps-rubella (MMR) vaccination,
for example, a child has a roughly one in 3,000 chance of developing a
fever that leads to a seizure.29 Such seizures do not
lead to any permanent neurological damage. Moreover, they also occur
more generally when kids develop high fevers—afflicting up to 5
percent of young children. Safety consideration for pregnant women
varies based on the nature of the disease (or pathogen) and vaccine
type. Generally, vaccines that contain killed (inactivated) viruses can
be given during pregnancy. Vaccines that contain live viruses are not
recommended for pregnant women. For many vaccines (e.g, influenza,
tetanus, diphtheria, whooping cough (pertussis)), vaccination is
absolutely recommended for the mother’s protection and for the
protection of the baby. For others, even though the vaccine may not be
recommended for pregnant women (e.g., human papillomavirus, measles,
mumps, rubella, varicella, and zoster) there is no cause for concern
from a safety perspective.30 In the final category,
the vaccine may be recommended for pregnant women if there is an obvious
risk factor (e.g., hepatitis A, hepatitis B, Hib and meningococcal
ACWY).31 Figure 2 provides a high-level evaluation of
the primary risk factors for both pregnant women and children for both
drug and vaccine therapy with consideration for the COVID-19 impact to
both populations.