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.