DISCUSSION
Epidemiological evidences show that SARS-CoV-2 infection in children is less frequent and severe than adults. Age-related ACE2 receptor expression and maturation, lymphocyte count and trained immunity might all be contributing factors to explain pediatric superiority35 with respect to early infectivity and disease severity. We can speculate that high ACE2 receptor concentrations, trained immunity and a constitutional high lymphocyte count in children may partially explain the mild disease observed in this group of patients but this is not yet established by definitive research. Real reasons will probably remain a mystery fortunately because the number of infected children is too low to allow good-sized immunological studies. This may be related to both exposure and host factors as has been previously speculated.14 Likewise, the age at which children appear similar to adults with respect to disease progression is not firmly established. One study suggesting that this may be true as early as 10 years of age will need to be challenged by additional studies that include patients other than overly infected and symptomatic pediatric patients.36 Children are usually well cared for at home and might have relatively fewer opportunities to expose themselves to pathogens and/or patients who are sick. This observation is heavily skewed by the experience thus far and will likely need to be re-evaluated as the virus moves to other geographic areas particularly LMICs where care, proximity and infection opportunities are likely very different.
Current risk assessment for pediatrics and pregnancy to COVID-19 treatment options suggests that the usual concerns for both these populations are relevant for many of the repurposed agents currently being evaluated. The disease itself does pose additional risks mostly due to its extensive distribution and effect on the inflammatory system particularly in later stages of duration. Unfortunately, the majority of single agent and combination drug trials excludes pediatric patients and pregnant women at present, though hopefully there will be an opportunity for prospective testing in both populations as one or more therapeutic options become viable. The same is true for vaccines of course. As has been the case for other antiviral drug therapies, successful treatment of SARS-CoV-2 likely involves drug combination, multimodal therapy. Similar to the experience with HIV, effective treatment likely lies with multiple mechanisms to kill the virus, stop the virus from entering cells and stop the virus from replicating. Also like HIV hopefully, choices of agents that represent the standard of care will be tailored to limit side effects and drug interaction potential and will also be tailored to the target population of interest which may present different benefit:risk profiles different from mainstream patients (i.e., pediatrics and pregnant women). Experience with HIV in the populations may also shed light on timing of therapy considerations37 or combination choices that may be given to women during pregnancy, to reduce the risk of vertical transmission to the child.38
Recent trends to share real world data (RWD) from COVID-19 patients is very encouraging in addition to the collaborative events in general. It provides a forum from which the available basic and clinical pharmacology can be linked to more rapidly pressure-test repurposed drugs and vaccines while providing a benchmark for new drugs and drug combinations for the purpose of future readiness. The PEDIATRIC COVID-19 Registry (https://www.pids.org/news/764-usa-pediatric-covid-19-registry.html) similarly creates a repository of surveyed pediatric patients treated for COVID-19. Under the umbrella of the Pediatric Infectious Diseases Transplant Network (PIDTRAN) and through its Coordinating Center at St. Jude Children’s Research Hospital, in collaboration with Children’s Hospital of Philadelphia, Seattle Children’s and Chicago Children’s Hospital survey data captures epidemiologic and clinical information about all cases of pediatric COVID-19 infections in the United States. Other efforts to accumulate COVID-19 RWD for evaluating real-time clinical performance of therapies representing the current standard of care and potentially guiding us on future pandemic readiness include the ISPY-2 for COVID accelerator, the CURE-ID and the COVID-19 Diagnostics Evidence Accelerator. CURE ID is an internet-based repository that lets the clinical community report novel uses of existing drugs for difficult-to-treat infectious diseases through a website, a smartphone or other mobile device. The platform enables the crowdsourcing of medical information from health care providers to facilitate the development of new treatments for neglected diseases. CURE ID is a collaboration between the FDA and the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH). FDA and NIH are also collaborating with the World Health Organization and the Infectious Disease Society of America to assess the global utility of the CURE ID. The Diagnostics Evidence Accelerator is organized by the Reagan-Udall Foundation for the FDA in collaboration with Friends of Cancer Research. The Diagnostics Evidence Accelerator is the companion project to the previously announced Therapeutic Evidence Accelerator, which brings together leading experts in health data aggregation and analytics in a unified, collaborative effort to share insights, compare results and answer key questions to inform the collective COVID-19 response. In addition, less traditional RWD sources such as patient-centric data39,40 and large-scale twitter feed data are coming to bear on quantifying COVID-19 prevalence and treatment response.5
On the vaccine front, as of July 2020, 205 vaccine candidates were in development, with 17 in human testing: two in Phase II efficacy and dose-testing studies in human subjects, five in Phase I–II safety and efficacy trials, and ten in Phase I trials.34 Early results are promising but still too preliminary to assess a viable clinical candidate. The National Institute of Allergy and Infectious Diseases (NIAID) has established a new clinical trials network that aims to enroll thousands of volunteers in large-scale clinical trials testing a variety of investigational vaccines and monoclonal antibodies intended to protect people from COVID-19. The COVID-19 Prevention Trials Network (COVPN)41 was established by merging four existing NIAID-funded clinical trials networks: the HIV Vaccine Trials Network (HVTN)42, based in Seattle; the HIV Prevention Trials Network (HPTN)43, based in Durham, N.C.; the Infectious Diseases Clinical Research Consortium (IDCRC)44, based in Atlanta; and the AIDS Clinical Trials Group, based in Los Angeles. The presumption that using real-world data can provide actionable information about the prevalence of SARS-CoV-2 in specific populations and highlight individual risk factors for patients, helping to improve our understanding of the disease, tailor public health interventions and strategies to mitigate risks for individuals and communities, and help stop the spread of SARS-CoV-2 is an important milestone for these efforts and may indeed provide a roadmap to handle future crisis situations. The evidence generated through the various RWD platforms is intended to be complementary to actual clinical studies that have been conducted or are underway as well as a mechanism to address questions not yet answered. One can only hope that the spirit of collaboration continues despite a devolving political landscape that makes collaboration and open science policies more difficult, especially in the face of a global pandemic.