Welcome to the third edition of the Center for Pediatric Clinical Development (CPCD) newsletter. This quarterly publication will keep you informed on who we are and what we are doing, as well as on key news in the world of pediatric clinical development. Future editions will explore topics and issues on pediatric research to keep you up to date.

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This edition comes to you in the midst of the COVID-19 global pandemic. As of publishing, we’ve included the most up-to-date data possible to introduce you to some topics of pediatric interest. However, as our understanding of this virus and its impact continues to evolve, so does the data surrounding COVID-19.

Edition Highlights:

New Regulatory Rules for the Development of Medicines under the COVID-19 Pandemic

The SARS-CoV-2 pandemic has affected to date more than 31,409,623 people worldwide (status 22 September 2020) including 7% children 1, and continues to present an extraordinary challenge to global health. Data on disease severity and pathogenesis of SARS-CoV-2 infection in children are limited. Overall, several large epidemiologic studies suggest that acute disease manifestations are substantially less severe in children than in adults, although there are reports of children with COVID-19 requiring intensive care unit (ICU)-level care. The reported number of COVID-19 deaths among children under the age 18 in the U.S. is less than 1% of reported COVID-19 deaths, even though children make up 22% of the U.S. population.

A large number of companies are developing treatments and vaccines for COVID-19. As of 22 Sept 2020 there are globally 38 candidates in clinical evaluation and 149 in preclinical evaluation. 2 The treatments under development include antivirals, monoclonal antibodies, convalescent plasma, immune modulators, stem cells, and products such as hydroxychloroquine.

Many applicants developing medicines for the treatment of COVID-19 are in the process of conducting clinical trials and/or approached regulatory authorities with their proposals for Phase 3 clinical trials.

As of mid-July, the FDA had reviewed more than 230 trials of potential therapies for COVID-19 and there are more than 510 drug development programs in planning.

As of 01 September 2020, the EMA has been in discussion with the developers of 38 potential COVID-19 vaccines and 158 potential COVID-19 treatments. These include immunomodulators, antivirals and hyperimmune serums. The EMA has also finalized 17 scientific advice procedures to provide developers with direction on the most appropriate methods and study designs for potential COVID-19 medicines. A further 22 such procedures are ongoing.

For the development of products for COVID-19, authorities have released specific guidance documents, implemented revised approval processes, and collaborate on an international level through e.g., the International Coalition of Medicines Regulatory Authorities (ICMRA). They invite developers of potential COVID-19 treatments and vaccines to consult for advice at an early stage to enable promising medicines to reach patients as soon as possible.

Development of products for COVID-19 — Guidance from Authorities

Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are providing developers of products for COVID-19 with guidance.

The FDA plays a critical role in protecting from threats such as COVID-19 pandemic and has issued in May 2020 a guidance to assist developers of treatments and prevention products, i.e., COVID-19: Developing Drugs and Biological Products for Treatment or Prevention Guidance for Industry. 3

As per the FDA guidance, children should not be categorically excluded from clinical trials of investigational COVID-19 products in which there is a prospect for direct benefit, on the contrary, sponsors are encouraged to discuss pediatric drug development with the FDA early in the course of the clinical development, including the potential for extrapolation of adult efficacy data, appropriate pharmacokinetic trials in the pediatric population in order to support dose selection, as well as the recommended size of the pre-approval safety database in children.

The EMA emphasizes the need for large, multi-national trials as these are most likely to generate the conclusive evidence needed to enable rapid development and approval of potential COVID-19 treatments.

The decision on the timing of initiating pediatric trials depend on several factors, including but not limited to the amount of available clinical and/or nonclinical safety data for the product. For example, if dosing recommendations for a drug are the same for adults and adolescents and there is sufficient prospect of benefit to justify the risks, then it might be appropriate to include adolescents in the initial phase 3 clinical trials. Sponsors are encouraged to submit an initial pediatric study plan (iPSP) as soon as practicable. For product for COVID-19, the FDA intends to work with sponsors to reach agreement on the iPSP and any pediatric trial protocols as quickly as possible to avoid any unnecessary delays in the initiation of trials or submission of any marketing application.

FDA also encourages the enrollment of pregnant and lactating individuals in the phase 3 (efficacy) clinical trials if appropriate.

Similar to FDA, the EMA is providing guidance for medicine developers to help speed up medicine and vaccine developments and approvals for COVID-19, i.e., “EMA initiatives for acceleration of development support and evaluation procedures for COVID-19 treatments and vaccines.” 4

The EMA emphasize the need for large, multi-national trials as these are most likely to generate the conclusive evidence needed to enable rapid development and approval of potential COVID-19 treatments. It also stresses the need to include all EU countries in these trials.

Establishing contact early in the development process is important for ensuring that developers can submit well prepared applications and make use of the accelerated procedures EMA has put in place for COVID-19 treatments and vaccines. These rapid procedures can accelerate every step of the regulatory pathway while ensuring that robust evidence on efficacy, safety and quality is generated to support scientific and regulatory decisions. They are available for initial marketing authorization applications and extension applications for authorized medicines that are being repurposed for the treatment of COVID-19. The rapid procedures range from rapid Scientific Advice, rapid agreement on pediatric investigation plans (PIPs) and rapid compliance check, through rolling review to accelerated assessment. The table below (Table 1) provides an overview of the procedures with details on the features for each procedure.

As per the FDA guidance, children should not be categorically excluded from clinical trials of investigational COVID-19 products in which there is a prospect for direct benefit, on the contrary, sponsors are encouraged to discuss pediatric drug development with the FDA early.

For the pediatric population, please note the considerably reduced timelines for the PIP process in comparison to the timelines for non COVID-19 products. There is no submission deadline, significantly reduced review times by the PDCO, 20 days in comparison to 120 days, and fast compliance check. All efforts are set to have a fast process. For companies developing their product for both the US and EU, the authorities have established a joint FDA/EMA procedure for the pediatric plans.

Table 1 overview of EMA rapid procedures
Figure 1 Remdesivir iPSP and PIP timelines

Joint FDA / EMA Procedure for Submitting Pediatric Development Plans for Products for COVID-19

The joint procedural information is available for medicine developers planning to submit a PIP to the EMA and an iPSP to the FDA for a COVID-19 vaccine or treatment. The Common Commentary was published on 2 June 2020. 5

The joint document aims to make it easier for developers to submit pediatric development plans simultaneously to the FDA and EMA, to help speed up the development and approval of COVID-19 treatments and vaccines.

Both, the FDA and EMA are encouraging medicine developers to submit PIPs and iPSPs early.

An example of “fast” iPSP and PIP agreements using the simultaneous submission is Remdesivir (Gilead) for the treatment of COVID-19. The iPSP was agreed within 7 weeks and the PIP within 4.5 weeks (Figure 1).

Global Collaboration for the Development of Products for COVID-19

During the ongoing COVID-19 pandemic, the International Coalition of Medicines Regulatory Authorities (ICMRA) is acting as a forum to support strategic coordination and international cooperation among global medicine regulatory authorities. The aim of the activities is to expedite and streamline the development, authorization and availability of COVID-19 treatments and vaccines worldwide.

ICMRA members, who represent 28 medicines regulatory authorities globally, as well as experts from the World Health Organization and the European Commission, discuss international alignment on COVID-19 policies in strategic meetings held every two weeks. These strategic discussions build on the knowledge and experience gained from the series of ICMRA workshops on COVID-19 medicine development held in March and April 2020. EMA and FDA are taking turns to chair these meetings.

In June 2020, ICMRA members committed to stepping up the global collaboration and prioritization of COVID-19 clinical trials, with the aim of expediting COVID-19 medicine and vaccine development and approval based on robust scientific evidence.

ICMRA members have reached agreements on several aspect of product development such as:

  • Agreement on acceptable clinical-trial endpoints to facilitate rapid and consistent clinical trials for COVID-19 treatments
    • It was reflected that in only 5 months into this pandemic with a new virus the understanding of the natural history of COVID-19 disease has progressed swiftly, but still a more granular characterization of the disease course and how to manage different patient’s phenotypes would be highly informative for clinical studies design of investigational COVID-19 treatments
    • The primary endpoint ideally should be clinically meaningful (capturing patient function as well as survival), but it also needs to be measurable, to be sufficiently sensitive to allow realistic sample sizes. A sensible and suitable way of handling the missing data / intercurrent events and mortality also needs to be defined
  • Progress is being made on:
    • Developing a pharmacovigilance network for vaccines for monitoring the safety and effectiveness of vaccines against COVID-19 in order to rapidly detect and minimize risks to patients
    • The establishment of international patient cohorts to share expertise and increase study power and data quality in order to meet regulatory requirements and address existing knowledge gaps
    • Carrying out research in pregnant women to examine the impact of both coronavirus disease and medication use on pregnant women infected with SARS-CoV-2 and on their unborn babies in order to support COVID-19 medicine development, risk management, and planning for safety monitoring of vaccines and therapeutics

For the collaboration on studies in pregnant women, a technical expert working group on COVID-19 and medicines in pregnancy was created to encourage international collaboration on studying the impact of COVID-19 infection and medicines in pregnancy and neonatal outcomes. Planned deliverables include the establishment of a worldwide network of data sources and the development of common protocol(s) or common data model(s) as appropriate, to enable meta-analyses across the different global regions. Moving forward, the aim is to set up a sustainable worldwide research network of data sources that can be mapped and leveraged for future drug safety evaluation in pregnancy. The inventory is planned to be ready by the end of August 2020. 6

Another aspect evaluated is the use of COVID-19 clinical trial master protocols around the world to accelerate the development and approval of potential treatments and vaccines against COVID-19. ICMRA members are currently working on a list of ongoing and planned COVID-19 clinical trials with master protocols in different countries and regions in order to compare the protocols and identify possible overlaps, for example regarding objectives and types of investigational agents studied. Regulators aim to update this list on a regular basis.

Clinical Trials Under the COVID-19 Pandemic

The COVID-19 pandemic has impacted clinical research and hence pediatric research. Authorities have early on issued guidance on how the management of clinical trials and participants during the COVID-19 pandemic can be performed. The guidance cover concrete changes and protocol deviations for dealing with extraordinary situations, such as the need for isolating participants, limited access to public spaces and the reallocation of healthcare professionals.

The guidance provides details on:

  • The distribution of medicines to trial participants, taking into account social-distancing measures and possible limitations at the trial site as well as site resources
  • The remote verification of source data (SDV) in the context of social distancing measures. This aims to facilitate activities that support the approval of COVID-19 and other life-saving medicines
  • Notifying authorities of urgent actions taken to protect trial participants against an immediate hazard, or of other changes taken to support patient safety or data robustness

The FDA and European Commission released guidance documents, and so did some further national authorities. Follow this link to FDA guidance version 02 July 2020 “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency” and the link to the EU Commission guidance Version 3 dated 28 April 2020.

Conclusion

In order to ensure the development of adequate medicines for the COVID-19 pandemic, authorities are working closely with the developers. They have reviewed their processes for these products in order to allow a fast development and have established a close collaboration on a global level to expedite and streamline the developments. The pediatric population has so far not been the first priority for developers may be mainly because of the substantially less severe cases seen in children than in adults. Authorities are requesting to not exclude the pediatric population from clinical trials of investigational COVID-19 products. Let’s ensure that the medicines developed will be developed and approved for children.

Pediatric Oncology and COVID-19

Figure 2 data from the global registry 600
COVID-19 Positive Cases by Age Group

In the midst of the COVID-19 global pandemic children’s lives are most notably being turned upside down: school closures, no playdates, no large scale Saturday night concert venues, and parents working from home! Gasp! While it still holds true that children are largely less symptomatically affected by COVID-19 than adults, the more recent verbalized concerns for unknown organ impact, long term implications, asymptomatic carriers, and the tragic death of a 6 week old child attributed to the virus in the US, possibly one of the youngest aged persons to die with COVID-19, has sparked renewed fears and concerns regarding the possible, though maybe not yet realized impact on our children. All children are vulnerable and made even more so by lack of information gathering, and review and application of our findings on a continual basis.

The Leukemia and Lymphoma Society cites that 80% of pediatric oncology survivors will suffer at least one significant late effect due to treatment for pediatric cancer as a child. Late effects are those effects that occur much later post initial treatment for cancer. Late effects caused by chemotherapy and/or radiation treatment can include heart disease, lung disease, and endocrine issues to name just a few. The pediatric oncology community prioritizes monitoring of short and long term effects, as well as late effects. So what about the impact for the child if he or she is afflicted with COVID-19 on top of their cancer diagnosis and therapies?

St. Jude’s Children’s Research Hospital and the International Society of Paediatric Oncology have united and created a global pediatric oncology-COVID-19 registry. Healthcare providers worldwide are invited to report any patient with a malignancy or prior hematopoietic stem cell transplant 19 years of age or younger at the time of a laboratory-confirmed SARS-CoV-2 infection. They emphasize two key points:

  1. Being an international effort and counting on robust participation and collaboration
  2. The pediatric hematology/oncology community will be provided with regularly updated summary information about reported cases, including numbers of cases by country, number of cases by treatment, etc. so the entire childhood cancer community has access to these data.

Once the COVID-19 positive pediatric oncology patient is identified the registry has three forms to be filled out and will be tracked. Forms include the diagnosis and presentation form, and the 30 and 60 days follow up forms. De-identified information includes such things as place of diagnosis, sex, primary or reinfection, type of positive samples obtained, underlying malignancy, what type of treatment at time of diagnosis, white blood cell values, known comorbidities, symptoms and length of symptoms, scan results, co-identified pathogens, and admission and hospital course.

Visualizing the data is even easier and can be accessed by anyone here. As of September 22, 2020 there are 878 COVID-19 positive cases with 39 countries reporting. (Figure 2).

Other pediatric registries exist. For example in the UK there is a pediatric oncology specific one here. There are also ones such as the Pediatric COVID-19 US Case registry here which is not tied to a specific pediatric patient sub-population and acknowledges that the pediatric presentation for COVID-19 is poorly defined as most cases are in adults.

Should Schools Re-Open During the COVID-19 Pandemic?

School closure

School closure during the COVID-19 pandemic has impacted children’s learning, physical and mental well-being, and safety. Re-opening of schools is therefore a priority only hampered by safety concerns. Younger children and those who don’t have access to remote learning (lack of device, Internet bandwidth, and social roadblocks) are the priority.

The majority of COVID-19 positive children have mild disease or are asymptomatic. But they could pass on the virus to adults, both in school (teaching and non-teaching staff) and at home.

A new report from AAP suggests that cumulative COVID-19 cases in children in the community have nearly tripled from 200,000 to >587,000 (9th July and 17-September, 2020). 7 As schools re-opened physically, this number has increased exponentially as reported in several countries.

Authorities have a big challenge in safely implementing the AAP recommendation for commencement of early in-person learning.8 There is increasing evidence that children of all ages can be infected and children older than 10 years play a role in the transmission of the virus. 9,10,11,12,13

The additional challenges in developing countries are unique in many ways. At least one-third of the world’s school-children – 463 million children globally — were unable to access remote learning when COVID-19 shuttered their schools.14

In low-income countries, families are large and multi-generational, opportunities for earning livelihood have diminished for adults, health infrastructure is often inadequate, social distancing is almost impossible to implement both in slums and in existing overcrowded school setting, etc. While most children in the urban cities may have been able to attend online classes, the story is quite different in the rural areas. Besides loss of learning, these children also missed out on nutritional benefits such as the midday meal program. Poor networks, erratic power supply, and natural calamities such as floods, cyclones, earthquakes, complete the list of their problems.

A recent UNICEF report states that 105 of a total of 134 countries (78%) that had closed schools have decided on a date to reopen schools, 59 of which have already done so. 15

Some examples of the status of school re-opening at the end of August reflects the range of approaches and success:

  • Japan, Taiwan, and Singapore are some of the countries that have successfully reopened schools.
  • Schools in Europe have reopened cautiously with smaller classes, shorter lessons, mask-wearing, and other safety measures to curb infection. But in Berlin, Germany, schools had to be closed just days after classes resumed when several COVID-19 positive cases were detected in students and staff.
  • In several US states, reopened schools had to be shut after students and staff tested positive for COVID-19, compounding the challenge.
  • In Israel, a ‘second-wave’ of infections has been directly linked to schools. Similar findings have also been reported from South Korea and South Africa.
  • In the UK, separate guidance for England, Scotland, Wales, and Northern Ireland are in place. In Scotland, schools reopened in August, along with some in Northern Ireland. England and Wales plan to open in September.
  • In Brazil, some states plan to resume in person classes, others continue online learning, while still others will adopt a graded return to physical classes based on the course of the pandemic.
  • In Canada, back to school is planned to start close to the usual time in September and each province has developed plans with a focus on how to quickly identify the inevitable cases that arise.
  • In some states in India, schools have partially reopened for senior students after 6 months, but attendance is very poor. This is because 75,000 to 90,000+ new COVID-19 positive cases are still being detected daily. Until schools reopen fully, online teaching and learning activities continue for the younger students. Fortunately, in some rural areas poor Internet connectivity was successfully solved by having televised lessons or recorded lessons heard over a loudspeaker by children gathered with social-distancing in open grounds.

Schools can reopen in a staggered manner only if they are made safe — including provision of basic facilities — access to hand hygiene, clean and safe drinking water and safe sanitation. Schools can also consider a one-way system in halls. They can ensure windows and doors open for ventilation, or even expand outdoor instruction. Whether single-seater desks placed six feet apart and plastic desk partition will be useful are unclear. It is also paramount that students as well as school staff should stay at home if sick (any symptoms of illness), or have been in close contact with a COVID-19 positive person.

The administration has its hands full. Limited and evolving insights into the ongoing pandemic continue to keep the situation fluid. In the meantime, if vaccines become available or herd immunity becomes a reality, the education problem will solve itself. Nothing can be better news.

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PRA's World Children's Day Xtalks Event

Defying Healthcare Disparities and Clinical Trial Barriers in Pediatric Populations
November 16th, 2020 | 10 AM EST

Topics to be discussed include:

  • Ongoing health disparities and social determinants
  • Diversity (and the lack thereof) in clinical trial participation
  • Inclusion of adolescents in adult clinical trials
  • Clinical trial education to the public
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XTalks Webinar
The RACE for Children Act: Early Global Impact and Ensuring Success with Pediatric Champions
December 17th, 2020 | 10:00-11:15 AM EST

Pediatric Site Network Update

Pediatric site network 452

The Pediatric Site Network continues to be an asset to PRA across multiple stages of drug development, clinical trial planning and delivery. This in-house network, built and maintained by the CPCD, allows us to augment our existing pediatric expertise with insights from research minded pediatric thought leaders. PRA has leveraged several PSN KOLs for early protocol consultation as well as to participate in several pediatric clinical trials that PRA has been awarded since our last newsletter.

Similar to what we witnessed in way of COVID-19 spreading across the globe, PSN sites’ capacity to continue to conduct clinical trials mirrored the spread. They have, however, been less affected directly than centers that treat adults. Most centers are involved in and conducting research related to COVID-19 is many ways.

In this newsletter, we highlight the work of one of our PSN sites, Sant Joan de Déu in Barcelona, Spain, which does outstanding research. With what they term the “Kids Corona platform,” Sant Joan de Déu has conducted a few very important studies that are one of a kind. In April they launched an in home study following 411 families that included a total of 724 children with at least one parent having been treated at their hospital with a confirmed COVID-19 diagnosis. The study also included pregnant women with a confirmed COVID-19 diagnosis treated at their hospital.The results concluded that children become infected similar to adults with a 17% infection rate within the domestic environment while COVID-19 affected 14% of pregnant women mostly mild or asymptomatic. Those cases that were most severe tendedto be during the third trimester.

Because it wasn’t possible to analyze child-to-child transmission during this in home study, the researchers launched a new study with the objective to do just that. Over the summer, with significant logistical support from the hospital’s research institute, 2,000 samples were collected from children ages 3 to 15 at 24 summer and sports camps on a weekly basis. The objective was to “see what happens to children when they are in an environment where COVID-19 circulates and that reproduces conditions similar to those that could be found at school in September.” This study is noted to be a first of its kind internationally. For more details please read here.

Figure 3 - Pediatric Site Network Membership

Articles, Blogs, and White Papers Published by CPCD Team in 2020

Additional publications from our CPCD team

PRA: Get Ready for the RACE Act

Collaboration, Not Competition, Will Bring Better Pediatric Medicines to Market

Pediatric Trials Require Specialized Endpoints

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RACE for Children Act in Effect!

The first two editions of our newsletter focused on pediatric oncology and the RACE for Children Act. It is now in effect and we are eager to achieve the pediatric oncology’s collective goal of getting up to date treatments to children with cancer.

If you have any questions, please do not hesitate to contact us at CenterPediatricClinDev@prahs.com.

The Center for Pediatric Clinical Development Team

The CPCD Team is led by Vice President Mark Sorrentino, MS, MD, with members from across the globe. If you need assistance with a pediatric study, have a personal interest in pediatrics, or would like more information, please contact us: CenterPediatricClinDev@prahs.com.

Mark Sorrentino baby

Mark Sorrentino, MS, MD
Vice President

Harris Dalrymple baby

Harris Dalrymple, PhD Law, PhD Medicine
Vice-Chair and Executive Director

Johnny Peppers baby

Johnny Peppers, PhD
Executive Director
Drug Development

Aparna Parikh baby

Aparna Parikh, MD, DCH, CCRA
Executive Director

Kirsten Sherman Cervati baby

Kirsten Sherman Cervati, BA, CCRP
PSN Lead, Senior Director

Missy Hansen baby

Missy Hansen
MSN, APRN, CNP
Pediatric Strategy Liaison

Heather Peterson baby

Heather Peterson, RN, BSN
Pediatric Strategy Liaison

Anne Behringer baby

Anne Behringer, Dr. rer. nat., Dipl.-Chem.
Executive Administrative Associate

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Jacqui Whiteway, PhD
Senior Pediatric Strategy Liaison

Jami Thompson baby

Jami Thompson
Senior Pediatric Site Network Specialist

Martine Dehlinger Kremer baby

Martine Dehlinger-Kremer, PhD
Vice President of Scientific Affairs, Pediatric Subject Matter Expert

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Jo Dewhurst, BSc (Hons), LLB Dip
Pediatric Strategy Liaison

Check out Mark and Missy's featured profiles

Interested in learning more about any of the information mentioned here, or have a suggestion for a topic you would like to see profiled?

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References

1 Source CDC, https://www.cdc.gov/covid-data-tracker/#demographics

2 WHO https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

3 https://www.fda.gov/media/137926/download

4 https://www.ema.europa.eu/en/documents/other/ema-initiativesacceleration-development-support-evaluation-procedures-covid-19-treatments-vaccines_en.pdf

5 https://www.fda.gov/media/138489/download

6 https://www.ema.europa.eu/en/news/global-regulatory-workshop-covid-19-real-world-evidence-observational-studies

7 https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report/

8 https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/covid-19-planning-considerations-return-to-in-personeducation-in-schools/

9 Szablewski CM, Chang KT, Brown MM, et al. SARS-CoV-2 Transmission and Infection Among Attendees of an Overnight Camp — Georgia, June 2020. MMWR Morb Mortal Wkly Rep 2020;69:1023–1025. DOI: http://dx.doi.org/10.15585/mmwr.mm6931e1externalicon

10 Park YJ, Choe YJ, Park O, et al.; COVID-19 National Emergency Response Center, Epidemiology and Case Management Team. Contact tracing during coronavirus disease outbreak, South Korea, 2020. Emerg Infect Dis 2020;26.

11 Stein-Zamir C, Abramson N, Shoob H, et al. A large COVID-19 outbreak in a high school 10 days after schools’ reopening, Israel, May 2020. Euro Surveill 2020;25. Epub July 23, 2020.

12 Park YJ, Choe YJ, Park O, Park SY, Kim YM, Kim J, et al. Contact tracing during coronavirus disease outbreak, South Korea, 2020. Emerg Infect Dis. 2020 Oct [date cited]. https://doi.org/10.3201/eid2610.201315)

13 Yonkers LM, Neilan AM, Bartsch Y, Patel AB, et al Pediatric SARS-CoV-2: Clinical Presentation, Infectivity, and Immune Responses, The Journal of Pediatrics (2020), doi: https://doi.org/10.1016/j.jpeds.2020.08.037.

14 https://www.unicef.org/press-releases/covid-19-least-third-worlds-schoolchildren-unable-access-remote-learning-during

15 https://www.unicef.org/coronavirus/what-will-return-school-during-covid-19-pandemic-look