Scientific Background:

COVID-19 is a global health crisis. The clinical characteristics, disease progression and
outcome in children and young adults appear significantly milder compared to older
individuals. Since first being reported in Wuhan, China in December 2019, COVID-19 has
rapidly spread, affecting over 200 countries worldwide. Children account for 1-5% of
diagnosed COVID-19 cases; although, many infected children may be asymptomatic and
therefore not diagnosed without population screening. Most infected children are likely
to be secondary cases and acquire the infection after exposure to a COVID-19 positive
adult, although there are no longitudinal data to confirm this yet. Intra-family
transmission may be important since, an unquantified proportion of children with COVID-19
areasymptomatic and may contribute to transmission. Multiple reports have demonstrated
that children and young adults have a milder form of the disease compared to adults.
Asymptomatic, mild and moderate infections comprise over 90% of all children who have
tested positive for COVID-19 with fewer severe and critical cases (5.9%) compared to
adults (18.5%). Given that severe COVID-19 appears very rare in children, an important
part of this assessment is ascertaining whether a positive RT-PCR for SARS-CoV-2 is a
clinically important factor in explaining the child's condition, or whether more occult
pathology may be responsible.

When the COVID-19 pandemic was first reported in Asia and initially spread throughout the
globe, pediatricians were grateful that children seemed to be only mildly symptomatic
with the infection in most cases. Then, an alarming warning came from the National Health
Service in England in April 2020 about cases of older school-aged children and
adolescents presenting with fever, hypotension, severe abdominal pain and cardiac
dysfunction who tested positive for SARS-CoV-2 infection either by nasopharyngeal RT-PCR
assay or by antibody testing. These children had laboratory findings of cytokine storm,
including high serum IL-6 levels, and generally required inotropic support to increase
cardiac output with rare need for extracorporeal membrane oxygenation. Almost all of
these children no longer required intensive care after only a few days and completely
recovered, although rare deaths resulted from complications of extracorporeal membrane
oxygenation. Case series of children presenting with this condition have now been
reported from the UK, Italy, Spain, France and Switzerland, and the United States. The
Centers for Disease Control and Prevention (CDC) has developed a case definition for use
in the United States and has termed the condition multisystem inflammatory syndrome in
children (MIS-C). If MIS-C is indeed related to infection with SARS-CoV-2, the
pathophysiological mechanism of disease is unclear.

Very few studies have addressed the immune responses to SARS-CoV2 (either humoral or cell
mediated immunity) in children. It is therefore necessary to study the immune responses
in asymptomatic infections, prior infections and MIS-C to understand the pathogenesis of
the disease.

Whole-genome sequencing of pathogens, especially viruses, is a powerful tool to generate
rapid information on outbreaks, resulting in effective understanding of the introduction
of the infection, dynamics of transmission, and impact of informed outbreak control
decisions. In- deed, genomic data can be used to identify pathogen genes interacting with
the host and allows characterisation of the more evolutionary constrained regions of a
pathogen genome, which should be preferentially targeted to avoid rapid drug and vaccine
escape mutants. (1). As the SARS-CoV-2 virus races around the world across the different
population, there needs to be a consolidated effort to understand the divergence of
demographically distributed strains. Since the transmission of SARS-CoV-2 is subject to
the extent of human interaction, the insights from the correlation of genetic diversity
would give vital information to tackle this transmission.

Recent published studies have reported that when comparing the 305 Indian SARS-CoV-2
genomes, a number of nucleotide variants or segregating sites being identified. Recent
literature report that there is the presence of multiple lineages of SARS-CoV-2 in India
in different geographic regions. 20A and 20B together (belonging to the former haplotype
of A2a) are the predominant haplotypes at pan India level and in each region.
Interestingly, the haplotypes were differentially distributed in different regions. While
the 20A were most abundant in Northern and Eastern India, 20B was found to be the most
abundant haplotype in Western and Southern India. The ancestral haplotypes of 19A and 19B
were mostly found in Northern and Eastern India, with 19B being the most abundant in the
latter region. While multiple haplotypes were introduced during the early part of the
outbreak in March-May 2020, the 20A, B and C haplotypes (A2a) became the predominant
haplotypes in all regions by June 2020. However, there are no studies that have
characterised the viral diversity in this pediatric population and its association with
immunological response and disease severity, in SARS-CoV-2 infected children.

Study objectives:

- To perform systems immunology of SARS-CoV2 infection, COVID-19 disease and MIS-C in
children

- To identify the SARS-CoV2 viral diversity in the pediatric population and correlate
with immune responses and disease severity.