Mild SARS-Cov-2 Infections and Neutralizing Antibody Titers
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Mild SARS-CoV-2 Infections and Neutralizing Antibody Titers Francesco Bonfante, DVM,a,* Paola Costenaro, MD, DTM&H,b,* Anna Cantarutti, PhD,c Costanza Di Chiara, MDb Alessio Bortolami, DVM, PhD,a Maria Raffaella Petrara, PhD,d Francesco Carmona, BSc,e Matteo Pagliari, PhD,a Chiara Cosma, MD,f Sandra Cozzani, MD,b Eva Mazzetto, DVM,a Giovanni Di Salvo, MD,g Liviana Da Dalt, MD,g Paolo Palma, MD,h,i Luisa Barzon, MD,j Giovanni Corrao,k,c Calogero Terregino, MD,a Andrea Padoan, MD,l Mario Plebani, MD,l,f Anita De Rossi, PhD,d,e Daniele Dona, MD, PhD,b Carlo Giaquinto, MDb BACKGROUND: Recent evidence suggests that neutralizing antibodies (nAbs) to severe acute abstract respiratory syndrome coronavirus 2 may persist over time; however, knowledge regarding pediatric subjects is limited. METHODS: A single-center, prospective observational study was conducted on 57 family clusters of coronavirus disease 2019, including children of neonatal and pediatric age attending the University Hospital of Padua (Italy). For each patient, blood samples were collected for both the quantification of nAbs through a plaque reduction neutralizing test and the detection of antinucleocapsid-spike protein immunoglobulin G and/or immunoglobulin M. RESULTS: We analyzed 283 blood samples collected from 152 confirmed coronavirus disease 2019 cases (82 parents and 70 children or older siblings of median age of 8 years, interquartile range: 4–13), presenting asymptomatic or with mildly symptomatic disease. Despite the decrease of immunoglobulin G over time, nAbs were found to persist up to 7 to 8 months in children, whereas adults recorded a modest declining trend. Interestingly, children aged <6 years, and, in particular, those aged <3 years, developed higher long-lasting levels of nAbs compared with older siblings and/or adults. CONCLUSIONS: Mild and asymptomatic severe acute respiratory syndrome coronavirus 2 infections in family clusters elicited higher nAbs among children. Full article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2021-051322 aDivision of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle Venezie, Padua, Italy; WHAT’S KNOWN ON THIS SUBJECT: Children and bDivision of Pediatric Infectious Diseases, Department for Women’s and Children’s Health, University of Padua, Padua, Italy; cLaboratory of Healthcare Research and Pharmacoepidemiology, Division of Biostatistics, adolescents usually present with asymptomatic or mild Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, coronavirus disease 2019 cases; however, they are key in Milan, Italy; dDepartment of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, transmitting severe acute respiratory syndrome University of Padua, Padua, Italy; eIstituto Oncologico Veneto, IRCCS, Padua, Italy; fDepartment of Laboratory coronavirus 2 infection. Recent findings revealed that g Medicine, University Hospital of Padua, Padua, Italy; Department for Women's and Children's Health, University of neutralizing antibodies (nAbs) persist up to 6 months in Padua, Italy; hAcademic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology and Vaccinology, convalescent adults; however, little is known about nAbs Bambino GesuChildren's Hospital, Rome, Rome, Italy; iDepartment of Systems Medicine, Tor Vergata University of Rome, Rome, Italy; jDepartment of Molecular Medicine, University of Padua, Italy; kNational Centre for Healthcare kinetics in children. l Research and Pharmacoepidemiology, University of Milano-Bicocca, Milan, Italy; Department of Medicine-DIMED, WHAT THIS STUDY ADDS: Younger children develop University of Padua, Italy, Padua, Italy higher levels of nAbs during the first 7 to 8 months after *Contributed equally as co-first authors asymptomatic or mild symptomatic coronavirus disease Drs Giaquinto and Dona designed the study and supervised the project; Dr De Rossi 2019, compared with older siblings and adults. The long- designed the study and contributed to the writing; Dr Costenaro designed the study and lasting levels of nAbs may lead to durable protection and wrote the manuscript; Dr Bonfante designed the study, performed the investigations, and higher viral clearance, reducing shedding and wrote the manuscript; Dr Di Chiara designed the study and provided reagents and transmission. samples; Dr Cozzani designed the study; Drs Bortolami, Pagliari, Mazzetto, and Barzon performed the investigations and provided reagents and samples; Dr Petrara performed To cite: Bonfante F, Costenaro P, Cantarutti A, et al. Mild the investigations, provided reagents and samples, and contributed to the writing; Dr SARS-CoV-2 Infections and Neutralizing Antibody Titers. Cantarutti performed the statistical analysis and wrote the manuscript; Prof Corrao Pediatrics. 2021;148(3):e2021052173 performed the statistical analysis; Dr Padoan contributed to the writing; Dr Plebani Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 148, number 3, September 2021:e2021052173 ARTICLE European countries have been facing naturally acquired nAbs among a Data Collection and Definitions a third wave of the novel cohort of family clusters of COVID- Information collected during the coronavirus disease 2019 (COVID- 19, including adults and children clinic was entered into a Web-based 19) pandemic and the spread of who recovered from asymptomatic database by using the Research several severe acute respiratory or mild symptomatic infections. Electronic Data Capture platform syndrome coronavirus 2 (SARS-CoV- (Vanderbilt University, Tennessee) 2) variants. With the advent of METHODS 1 hosted in the server of the vaccines, longitudinal studies of University of Padova. For this Study Design and Population both convalescent and vaccinated study, data were collected patients are of fundamental A single-center, prospective study retrospectively from the existing importance to understand the was conducted on Italian family clinical files and analyzed kinetics of humoral response and clusters of COVID-19 attending the anonymously. Subjects were infer correlates of protection for COVID-19 Family Cluster Follow-up considered patients with confirmed both infection and disease. In this Clinic, at the Department of COVID-19 if they had a record of respect, the titration of neutralizing Women’s and Children’s Health of virological positivity for SARS-CoV- antibodies (nAbs) is key to the University Hospital of Padua 2 by real-time polymerase chain determine the concentration of (Veneto Region, Italy). From March reaction (RT-PCR) according to antibodies preventing cells to be 2 1, 2020 to September 4, 2020, 57 routine diagnostic molecular infected by SARS-CoV-2. 16 families were enrolled meeting the protocols and/or resulted positive by either of the 2 Studies including convalescent following inclusion criteria: (1) serological tests adopted in this adults reported that humoral having children of pediatric age < study. For each confirmed COVID- immunity against SARS-CoV-2 may (aged 15 years); (2) any family 19 case, a baseline date was be short-lived, particularly in member (eg, mother and/or father – defined as follows: (1) for persons with mild illness.3 5 and/or any son or daughter) with a symptomatic cases, the first date However recent findings provided history of COVID-19. Families were between the onset of symptoms or evidences of nAbs persisting up to 6 enrolled in the program 4 to 6–10 thedateoffirstpositiveSARS-CoV- months, as with seasonal and 8 weeks after the end of either 2 molecular assay result; (2) for SARS-like coronavirus infection, isolation or hospitalization and after asymptomatic cases: the date of the after which nAbs can persist, referral from the family pediatrician. first positive molecular assay result respectively, up to 1 or several Evaluation of children and relatives 11,12 or, in those with only serologically years. included data collection on confirmed COVID-19 and with demographic parameters and past negative or undetermined nasal- SARS-CoV-2 infection in children is medical history, clinical evaluation 13 pharyngeal swab (NPS) results, by less severe than in adults, and the collection of a blood sample the family outbreak temporal resulting in underdiagnosis given for a characterization of the immune sequence, coinciding with the date the mild or asymptomatic clinical response to SARS-CoV-2. All subjects 14 of symptoms onset in a virologically course. However, children and aged >18 years, including older adolescents are key in the confirmed SARS-CoV-2 family siblings and parents, and legally transmission of infection.15 Little is outbreak (Supplemental Fig 6). authorized representatives of known about the kinetics of SARS- Subjects who were asymptomatic subjects aged <18 years, were CoV-2 nAbs in pediatric populations. and had no analytical evidence of informed of the research proposal Understanding the differences in the SARS-CoV-2 infection were and provided written consent for antibody response between adults considered to not have COVID-19. the collection and use of biological and children has important scientific The severity of COVID-19 was specimens and routine patient-based and public health implications, scored as mild, moderate, severe, or including design of risk-based data for research purposes. Families critical, following the World Health 17 surveillance programs, cost-effective were invited to return to the clinic Organization