RESULTS
The comparison of COVID1-19 disease progression between adults and children as summarized in Table 1 is clearly dominated by the early experience with the virus and mostly influenced by the early experience in China. As such, it is currently unknown how generalizable this evaluation will be to later stages of the pandemic experience (i.e., second wave of transmission) or even other parts of the world as the virus is transmitted more extensively to low and middle income countries and potentially mutates. Another interesting factor to re-examine over time is the extent to which other comorbidities and conditions play a role in the most serious disease trajectories for both pediatric and adult populations. The inflammatory component of the disease progression and patient susceptibility seems intimately correlated to severe cases in adults (e.g., cardiovascular events including stroke) and children (e.g. Kawasaki’s disease and PIMS). Emerging data from case studies is also changing how the medical community revisits early assumptions regarding viral transmission. Recent evidence from a single case study thus far32 suggests that SARS-CoV-2 also causes maternal viremia, placental infection demonstrated by immunohistochemistry and very high viral load; placental inflammation, as shown by histological examination and immunohistochemistry, and neonatal viremia following placental infection which is in contrast to early views on maternal – neonatal transmission. This would also seemingly be corroborated by the multisystem inflammatory syndrome observed in children in New York State.33
Drug candidates for early consideration of treatment of COVID-19 have been predominantly comprised of repurposed drugs. As these typically represent drugs either approved for other indications or drugs where a significant amount of experience has been obtained, there is typically a fair amount of data to be evaluated some of which may be relevant for extrapolation for pediatric patients or pregnant women. Table 4 summarizes the list of common repurposed drugs for consideration of use to treat COVID-19. Thirteen of the repurposed drugs or drug combinations are indicated for use in pediatrics in some age category (2 more exclusively in Japan, 1 exclusively in the EU) albeit for indications other than COVID-19; 10 of these are indicated for use in pregnant women (1 exclusively in Japan). Remdesivir has been granted investigational use only for pediatrics and pregnancy and has not been formally approved for either. Even in cases where these drugs are indicated in the populations, source data from which safety and or dosing could be extrapolated for use in COVID-19 in sparse. While many of the drugs listed are in fact listed as suitable for use in pregnant women under certain conditions (Categories A, B and C) most of these also reflect risk assessment based on preclinical toxicology studies and not actual clinical use in pregnant women.
Regarding vaccines, Table 5 lists the most promising vaccine candidates entering clinical stage testing for prevention against COVID-19. As the table indicates, vaccine candidates come from varied origins around thew world (EU, US, Japan, and China) and reflect government, private sector, and academic stakeholders either separately or in partnership. The list of candidates also reflects varied approaches including novel technologies and traditional vaccine strategies including recombinant-protein based vaccines, replicating or non-replicating viral vector-based vaccines, DNA vaccines, and mRNA vaccines (mostly focused on the spike glycoprotein or receptor binding domain), live attenuated vaccines, and inactivated virus vaccines. While all candidates are being evaluated in ongoing trials which can be identified in the National Library of Medicine’s ClinicalTrials.gov website, the underlying preclinical data is kept with the study sponsors for now as none of these are approved yet. Most of these trials exclude both children and pregnant women but there are at least plans to include younger patients in future trials as viable vaccine candidates become more well defined. Protocols also require contraception from both men and women planning to conceive around the trial and breast-feeding women are commonly excluded from trials as well.
Early results from vaccine trials are focused on safety and proof of immune response to vaccination. Thus far, the usual safety related findings for vaccines have been generated with injection site reaction being the most common event. The most common injection site adverse reaction has been pain; the most-commonly reported systematic adverse reactions have been fever, fatigue, headache, and muscle pain.34 Most adverse reactions that reported have been mild or moderate in severity.
Finally, Table 6 shows the current list of ongoing drug combination trials from industrial and academic collaboration and investigator-initiated trials respectively which again are mostly reflective of repurposed drug candidates listed in Table 4. The primary driver for such trials is of course the attempt to combat the virus at multiple points in its life cycle while hopefully minimizing drug interaction potential. Some, but not all of these trials, include pharmacokinetic sampling to assess whether presumed target exposures are achieved but again the vast majority of them are not conducted in pediatric patients or pregnant women leaving an extrapolation approach to bridge this gap should outcomes look favorable. While searching for these trials through the end of July 2020 is difficult given the number of global stakeholders it is also immediately clear that the list immediately becomes outdated given the pace of R&D during the pandemic. In review, it is somewhat disappointing that the majority of current study designs for these trials are not novel and few adaptive trials have been proposed or conducted.