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.