key: cord-0979483-7e59yddo
authors: Dien Bard, J.; Bootwalla, M.; Leber, A.; Planet, P.; Moustafa, A.; Harris, R.; Chen, P. Y.; Shen, L.; Ostrow, D.; Maglinte, D.; Flores, J.; Somak, R.; Ranganathan, S.; Perlman, E.; Zheng, X.; Selvarangan, R.; Delaney, M.; Campos, J.; Drew, M.; LoTempio, J.; Dunn, J.; Jung, S.; Dominguez, S.; Judkins, A.; Gai, X.
title: Emergence of SARS-CoV-2 variants of concern in the pediatric population of the United States
date: 2021-05-24
journal: nan
DOI: 10.1101/2021.05.22.21257660
sha: ae890d5d08f2bd48e7cd671b5b43b4a543bef80b
doc_id: 979483
cord_uid: 7e59yddo

The evolution of SARS-CoV2 virus has led to the emergence of variants of concern (VOC). Children, particularly <12 years old not yet eligible for vaccines, continue to be important reservoirs of SARS-CoV-2 yet VOC prevalence data in this population is lacking. We report data from a genomic surveillance program that includes 9 U.S. children's hospitals. Analysis of SARS-CoV-2 genome from 2119 patients <19 years old between 03/20 to 04/21 identified 252 VOCs and 560 VOC signature mutations, most from 10/20 onwards. From 02/21 to 04/21, B.1.1.7 prevalence increased from 3.85% to 72.22% corresponding with the decline of B.1.429/B.1.427 from 51.82% to 16.67% at one institution. 71.74% of the VOC signature mutations detected were in children <12 years old, including 33 cases of B.1.1.7 and 119 of B.1.429/B.1.427. There continues to be a need for ongoing genomic surveillance, particularly among young children who will be the last groups to be vaccinated.

The pandemic has afforded an unprecedented opportunity to observe the emergence and evolution of variants of concern (VOC) and variants of interest (VOI) through genomic surveillance. These VOCs were found to have significantly increased transmissibility and potential for immune escape (1, 2) . Continued high transmission rates in the U.S. increases concern for domestic VOCs such as the recently reported B.1.1.7 sub-lineage with spike protein D178H and membrane protein V70L mutations (3) . Rates of vaccination are also slowing in the U.S. with estimate decline rates of 20-30%. In addition, children <12 years of age currently remain ineligible for vaccination. A further complication is prolonged COVID-19 infection in immunocompromised children with increased mutation rates, serving as potential reservoir of novel VOCs (4) . Therefore, early detection of VOCs/VOIs and mutations in children is critical for providers and institutions. However, to date pediatric populations have not been a focus of genomic surveillance efforts.

We established a pediatric SARS-CoV-2 genomic surveillance program including 9 geographically diverse children's hospitals in the U.S (Supplementary Figure 1 ) that serve a socioeconomically diverse and underrepresented population. This cohort is also temporally diverse, comprising samples collected from over a 13-month timeframe (03/20 to 04/21) affording the opportunity to observe the emergence of mutations over time. Whole genome sequencing (WGS) as previously described (5) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 24, 2021. ; https://doi.org/10.1101/2021.05.22.21257660 doi: medRxiv preprint institutions (N=450). The median age of patients was 6.9 years (5 days-18 years).

Reasons for SARS-CoV-2 testing include symptomatic presentation, pre-procedural asymptomatic screening, and surveillance.

We analyzed the viral genomes to identify known VOC and key mutations associated with the VOC/VOI (N501Y, E484K, L452R)(6,7,8) and identified 560 key mutations and 252 VOCs total (Supplementary Table 1 Table 2 ). Data report that B.1.429/B.1.427 lineage is 20% more transmissible and demonstrates increased resistance to certain monoclonal antibodies 1 .

Beginning on 11/20 we also observed a significant increase in N501Y mutation in the spike protein, a key mutation found in the VOCs B. Table   2 ). Interestingly, we identified one B.1.1.7 isolate that also harbored the E484K spike mutation(9). Finally, over the period 10/20 to 04/21 we identified several isolates harboring the Q677H or Q677P mutation with only a modest increase (1.04 to 5.56%).

These mutations were reported from Louisiana and New Mexico but appears to be more widespread already in other states(10).

A key finding is that nearly three-quarters (70.70%, 456/645) of the key mutations is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 24, 2021. ; https://doi.org/10.1101/2021.05.22.21257660 doi: medRxiv preprint emergence of VOCs/VOIs in pediatric patients across diverse geographies and socioeconomic populations in the US. In conjunction with growing evidence for the risk of emergence of VOCs among chronically infected immunocompromised children, this report highlights the need for ongoing genomic epidemiological surveillance among pediatric populations who will be among the last groups to receive vaccination and who are key to ending this pandemic.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Prevalence of N501Y, E484K, L452R and Q677H/P identified by SARS-CoV-2 whole genome sequencing (WGS) compared to wild-type (WT) SARS-CoV-2 isolates were tested by WGS in pediatric patients <19 years of age seen at 9 Children's Hospital in the U.S. Wild-type isolates were defined as a SARS-CoV-2 isolate that does not carry any VOC signature mutations. All samples (ALL) were compared to samples tested at is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 24, 2021. ; https://doi.org/10.1101/2021.05.22.21257660 doi: medRxiv preprint

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature

SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

Rapidly emerging SARS-CoV-2 B.1.1.7 sub-lineage in the United States of America with spike protein D178H and membrane protein V70L mutations

Increased viral variants in children and young adults with impaired humoral immunity and persistent SARS-CoV-2 infection: A consecutive case series. EBioMedicine

High Prevalence of SARS-CoV-2 Genetic Variation and D614G Mutation in Pediatric Patients with COVID-19. Open Forum Infectious Diseases

Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant

 Supplementary Figure 1 . Geographical distribution of 9 Children's Hospitals in the U.S. Whole genome sequence and genomic analysis was performed on a total of 2119 SARS-CoV-2 isolates from 9 geographically diverse pediatric institutions: 1. Children's Hospital Los Angeles; 2. Children's Hospital Colorado; 3. Texas Children's Hospital; 4. Children's Mercy; 5. Lurie Children's Hospital; 6. Cincinnati Children's Hospital; 7. Nationwide Children's Hospital; 8. Children's National Hospital; 9. Children's Hospital of Philadelphia. The pediatric institutions are highlighted (in color) were merged with subsampled genomes carrying identical haplotypes from the same cities (in grey). The dot sizes are representative of the resulting number of genomes per city.