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Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols.

Abstract Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when

BackgroundFamily clusters offer a good opportunity to study viral transmission in a stable setting. We aimed to analyze the specific role of children in transmission of SARS-CoV-2 within households.MethodsA prospective, longitudinal, observational study, including children with documented acute SARS-CoV-2 infection attending 22 summer-schools in Barcelona, Spain, was performed. Moreover, other patients and families coming from other school-like environments that voluntarily accessed the study were also studied. A longitudinal follow-up (5 weeks) of the family clusters was conducted to determine whether the children considered to be primary cases were able to transmit the virus to other family members. The household reproduction number (Re*) and the secondary attack rate (SAR) were calculated.Results1905 children from the summer schools were screened for SARS-CoV-2 infection and 22 (1.15%) tested positive. Moreover, 32 additional children accessed the study voluntarily. Of these, 37 children and their 26 households were studied completely. In half of the cases (13/26), the primary case was considered to be a child and secondary transmission to other members of the household was observed in 3/13, with a SAR of 14.2% and a Re* of 0.46. Conversely, the SAR of adult primary cases was 72.2% including the kids that gave rise to the contact tracing study, and 61.5% without them, and the estimated Re* was 2.6. In 4/13 of the paediatric primary cases (30.0%), nasopharyngeal PCR was persistently positive > 1 week after diagnosis, and 3/4 of these children infected another family member (pConclusionsChildren may not be the main drivers of the infection in household transmission clusters in the study population. A prolonged positive PCR could be associated with higher transmissibility.

The increased incidence of COVID-19 cases and deaths in Spain in March 2020 led to the declaration by the Spanish government of a state of emergency imposing strict confinement measures on the population. The objective of this study was to characterize the nasopharyngeal microbiota of children and adults and its relation to SARS-CoV-2 infection and COVID-19 severity during the pandemic lockdown in Spain. This cross-sectional study included family households located in metropolitan Barcelona, Spain, with one adult with a previous confirmed COVID-19 episode and one or more exposed co-habiting child contacts. Nasopharyngeal swabs were used to determine SARS-CoV-2 infection status, characterize the nasopharyngeal microbiota and determine common respiratory DNA/RNA viral co-infections. A total of 173 adult cases and 470 exposed children were included. Overall, a predominance of Corynebacterium and Dolosigranulum and a limited abundance of common pathobionts including Haemophilus and Streptococcus were found both among adults and children. Children with current SARS-CoV-2 infection presented higher bacterial richness and increased Fusobacterium, Streptococcus and Prevotella abundance than non-infected children. Among adults, persistent SARS-CoV-2 RNA was associated with an increased abundance of an unclassified member of the Actinomycetales order. COVID-19 severity was associated with increased Staphylococcus and reduced Dolosigranulum abundance. The stringent COVID-19 lockdown in Spain had a significant impact on the nasopharyngeal microbiota of children, reflected in the limited abundance of common respiratory pathobionts and the predominance of Corynebacterium, regardless of SARS-CoV-2 detection. COVID-19 severity in adults was associated with decreased nasopharynx levels of healthy commensal bacteria.

• Self-collected nasal and saliva samples can be used for SARS-CoV-2 screening. • Self-collected nasal and saliva specimens had a 99% and 90% sensitivity, respectively. • Nasopharyngeal swab viral loads correlate better with nasal than saliva. • Viral load correlations are poorer at day 7, when lower viral loads are observed. [ABSTRACT FROM AUTHOR]

Background: Mass testing for early identification and isolation of infectious COVID-19 individuals is efficacious for reducing disease spread. Antigen-detecting rapid diagnostic tests (Ag-RDT) may be suitable for testing strategies; however, benchmark comparisons are scarce.Methods: We used 286 nasopharyngeal specimens from unexposed asymptomatic individuals collected between December 2020 and January 2021 to assess five Ag-RDTs marketed by Abbott, Siemens, Roche Diagnostics, Lepu Medical, and Surescreen.Results: For the overall sample, the performance parameters of Ag-RDTs were as follows: Abbott assay, sensitivity 38.6% (95%CI 29.1-48.8) and specificity 99.5% (97-100%); Siemens, sensitivity 51.5% (41.3-61.6) and specificity 98.4% (95.3-99.6); Roche, sensitivity 43.6% (33.7-53.8) and specificity 96.2% (92.4-98.5); Lepu, sensitivity 45.5% (35.6-55.8) and specificity 89.2% (83.8-93.3%); Surescreen, sensitivity 28.8% (20.2-38.6) and specificity 97.8% (94.5-99.4%). For specimens with cycle threshold (Ct) <30 in RT-qPCR, all Ag-RDT achieved a sensitivity ≥70%. The modelled negative- and positive-predictive value for 1% prevalence were >99% and <50%, respectively.Conclusions: When screening unexposed asymptomatic individuals, two Ag-RDTs achieved sensitivity ≥80% for specimens with Ct<30 and specificity ≥96%. The estimated negative predictive value suggests the suitability of Ag-RDTs for mass screenings of SARS-CoV-2 infection in the general population. [ABSTRACT FROM AUTHOR]

Background: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results., Methods: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022., Results: Five included studies from 4 countries enrolled and transfused 2620 adult patients. Comorbidities were present in 1795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14 580 in diverse assays. One hundred sixty of 1315 (12.2%) control patients were hospitalized, versus 111 of 1305 (8.5%) CCP-treated patients, yielding a 3.7% (95% confidence interval [CI], 1.3%-6.0%; P = .001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95% CI, 4.0%-11.1%; P = .0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment >5 days after symptom onset or in those receiving CCP with antibody titers below the median titer., Conclusions: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher., Competing Interests: Potential conflicts of interest. R. L. has received fees from Pfizer for serving as subinvestigator of a COVID vaccine trial. F. P. has received fees from Pfizer for serving as a principal investigator for a COVID vaccine trial. D. J. S. is a founder and board member of AliquantumRx with stock options; Hemex Health malaria diagnostics consulting; royalties for malaria diagnostic test control standards from Alere (Binax Inc/D/B/A Inverness Medical); consulting fees for legal malaria case from Mabrey Firm (2019); the following grants or contracts: NIH/NIAID R01AI150763, NIH R21TR001737, NIH R01AI111962, DOD TB210115 (CDMRP Tick-Borne Disease Research Program); the following patents: USP 9642865 (issued 9 May 2017, New angiogenesis inhibitors), USP 7270948 (issued 18 September 2007, Detection of malaria parasites by laser desorption mass spectrometry), Salts and polymorphs of cethromycin for the treatment of disease (pending, application 20210163522), and Macrolide compounds and their use in liver stage malaria and related disease (pending, application PCT/US2015/046665); and participation on 2018 NIAID Safety Monitoring Committee/Independent Safety Monitor Intramural, all outside the submitted work. B. J. A. R. reports advisory board membership for Roche and AstraZeneca on a COVID-19 therapy; membership on a data and safety monitoring board (DSMB) for Exevir; consulting fees from Roche and AstraZeneca; grants or contracts and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Gilead Sciences; and support for attending meetings and/or travel from Pfizer. J. J. Z. reports consulting fees from City of Hope; cell therapy consultant; participation on DSMB for the PACER trial; DSMB for the Tolerant trial; and advisory boards for Sanofi and Sobi. L. J. D. reports the following grants or contracts: 75A50120C00094 (BARDA), Collection, testing, and provision of COVID-19 convalescent plasma for NHLBI/NIH (C3PO) through America's Blood Centers; US Veterans Health Administration, Pittsburgh (contract number 36C24E20D0027, VA CURES-1); and Vanderbilt University (Collection, testing, and provision of COVID-19 convalescent plasma for Association of Convalescent Plasma Treatment with Mortality and Clinical Trajectory in Patients Hospitalized with COVID-19 in the Community Setting). B. P. reports the following grants or contracts: COVID Trials, Incyte, Parexel, Novartis Pharmaceuticals, Partner Therapeutics, Fulcrum Therapeutics (to University Health Science Center), and Pulmonary Hypertension Trials, United Therapeutics, GlaxoSmithKline, Insmed, Merck Sharp & Dohme (to University of Texas Health Center). C. W. C. reports consulting honorarium for participation on NHLBI ACTIV4 CONNECTS Steering Committee. I. E. reports support for attending meetings and/or travel for 50 Congreso Argentino de Medicina Respiratoria 2022, Abstract Scholarship, American Thoracic Society, International Conference in Philadelphia, 2020 Assembly on Pediatrics. G. P. M. reports grants or contracts from Pfizer, Moderna, Medicago, and Merck for clinical research (as principal investigator), and payment for presentations from Moderna. D. O. reports consulting fees paid to author from the Fight Infectious Diseases Foundation and the Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol. B. R. M. reports the following grants or contracts: NIH/NIAID R01AI150763, NIH R21TR001737, NIH R01AI111962, and DOD TB210115 (CDMRP Tick-Borne Disease Research Program). D. W. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AstraZeneca, and support for attending meetings and/or travel from Laboratorios Raffo. C. R. reports grants or contracts from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, AIDSfonds, and Health∼Holland; participation on a DSMB or advisory board as well as support for attending meetings and/or travel from Gilead Sciences and ViiV Healthcare; and gifts for the #awarehivukraine foundation. M. A. H. reports grants or contracts from Gilead, Insmed, and AN2 Therapeutics, as well as participation on the AIDS Clinical Trials Group Tuberculosis Transformative Science Group Study Monitoring Committee. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection., Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141., Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, -3.6%; 95% CI -14.6% to 7.3%, p  = 0.53; 2 g C19-IG20% vs placebo, 1.1%; -9.6% to 11.9%, p  = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported., Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19., Funding: Grifols., Competing Interests: EM, MT, NC, AS, and YT were employees from Grifols. The rest of authors declared no conflict of interest., (© 2023 The Authors.)

Background: Family clusters offer a good opportunity to study viral transmission in a stable setting. We aimed to analyze the specific role of children in transmission of SARS-CoV-2 within households., Methods: A prospective, longitudinal, observational study, including children with documented acute SARS-CoV-2 infection attending 22 summer-schools in Barcelona, Spain, was performed. Moreover, other patients and families coming from other school-like environments that voluntarily accessed the study were also studied. A longitudinal follow-up (5 weeks) of the family clusters was conducted to determine whether the children considered to be primary cases were able to transmit the virus to other family members. The household reproduction number (Re*) and the secondary attack rate (SAR) were calculated., Results: 1905 children from the summer schools were screened for SARS-CoV-2 infection and 22 (1.15%) tested positive. Moreover, 32 additional children accessed the study voluntarily. Of these, 37 children and their 26 households were studied completely. In half of the cases (13/26), the primary case was considered to be a child and secondary transmission to other members of the household was observed in 3/13, with a SAR of 14.2% and a Re* of 0.46. Conversely, the SAR of adult primary cases was 72.2% including the kids that gave rise to the contact tracing study, and 61.5% without them, and the estimated Re* was 2.6. In 4/13 of the paediatric primary cases (30.0%), nasopharyngeal PCR was persistently positive > 1 week after diagnosis, and 3/4 of these children infected another family member (p<0.01)., Conclusions: Children may not be the main drivers of the infection in household transmission clusters in the study population. A prolonged positive PCR could be associated with higher transmissibility., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Mele-Casas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Convalescent plasma has been proposed as an early treatment to interrupt the progression of early COVID-19 to severe disease, but there is little definitive evidence. We aimed to assess whether early treatment with convalescent plasma reduces the risk of hospitalisation and reduces SARS-CoV-2 viral load among outpatients with COVID-19., Methods: We did a multicentre, double-blind, randomised, placebo-controlled trial in four health-care centres in Catalonia, Spain. Adult outpatients aged 50 years or older with the onset of mild COVID-19 symptoms 7 days or less before randomisation were eligible for enrolment. Participants were randomly assigned (1:1) to receive one intravenous infusion of either 250-300 mL of ABO-compatible high anti-SARS-CoV-2 IgG titres (EUROIMMUN ratio ≥6) methylene blue-treated convalescent plasma (experimental group) or 250 mL of sterile 0·9% saline solution (control). Randomisation was done with the use of a central web-based system with concealment of the trial group assignment and no stratification. To preserve masking, we used opaque tubular bags that covered the investigational product and the infusion catheter. The coprimary endpoints were the incidence of hospitalisation within 28 days from baseline and the mean change in viral load (in log 10 copies per mL) in nasopharyngeal swabs from baseline to day 7. The trial was stopped early following a data safety monitoring board recommendation because more than 85% of the target population had received a COVID-19 vaccine. Primary efficacy analyses were done in the intention-to-treat population, safety was assessed in all patients who received the investigational product. This study is registered with ClinicalTrials.gov, NCT04621123., Findings: Between Nov 10, 2020, and July 28, 2021, we assessed 909 patients with confirmed COVID-19 for inclusion in the trial, 376 of whom were eligible and were randomly assigned to treatment (convalescent plasma n=188 [serum antibody-negative n=160]; placebo n=188 [serum antibody-negative n=166]). Median age was 56 years (IQR 52-62) and the mean symptom duration was 4·4 days (SD 1·4) before random assignment. In the intention-to-treat population, hospitalisation within 28 days from baseline occurred in 22 (12%) participants who received convalescent plasma versus 21 (11%) who received placebo (relative risk 1·05 [95% CI 0·78 to 1·41]). The mean change in viral load from baseline to day 7 was -2·41 log 10 copies per mL (SD 1·32) with convalescent plasma and -2·32 log 10 copies per mL (1·43) with placebo (crude difference -0·10 log 10 copies per mL [95% CI -0·35 to 0·15]). One participant with mild COVID-19 developed a thromboembolic event 7 days after convalescent plasma infusion, which was reported as a serious adverse event possibly related to COVID-19 or to the experimental intervention., Interpretation: Methylene blue-treated convalescent plasma did not prevent progression from mild to severe illness and did not reduce viral load in outpatients with COVID-19. Therefore, formal recommendations to support the use of convalescent plasma in outpatients with COVID-19 cannot be concluded., Funding: Grifols, Crowdfunding campaign YoMeCorono., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Understanding the role of children in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is critical to guide decision-making for schools in the pandemic. We aimed to describe the transmission of SARS-CoV-2 among children and adult staff in summer schools., Methods: During July 2020, we prospectively recruited children and adult staff attending summer schools in Barcelona who had SARS-CoV-2 infection. Primary SARS-CoV-2 infections were identified through (1) a surveillance program in 22 summer schools of 1905 participants, involving weekly saliva sampling for SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) during 2-5 weeks; and (2) cases identified through the Catalonian Health Surveillance System of children diagnosed with SARS-CoV-2 infection by nasopharyngeal RT-PCR. All centers followed prevention protocols: bubble groups, handwashing, face masks, and conducting activities mostly outdoors. Contacts of a primary case within the same bubble were evaluated by nasopharyngeal RT-PCR. Secondary attack rates and the effective reproduction number in summer schools (Re*) were calculated., Results: Among the >2000 repeatedly screened participants, 30 children and 9 adults were identified as primary cases. A total of 253 close contacts of these primary cases were studied (median, 9 [interquartile range, 5-10] for each primary case), among which 12 new cases (4.7%) were positive for SARS-CoV-2. The Re* was 0.3, whereas the contemporary rate in the general population from the same areas in Barcelona was 1.9., Conclusions: The transmission rate of SARS-CoV-2 infection among children attending school-like facilities under strict prevention measures was lower than that reported for the general population. This suggests that under preventive measures schools are unlikely amplifiers of SARS-CoV-2 transmission, supporting current recommendations for school opening., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Scarce data are available on what variables affect the risk of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the development of symptomatic COVID-19, and, particularly, the relationship with viral load. We aimed to analyse data from linked index cases of COVID-19 and their contacts to explore factors associated with transmission of SARS-CoV-2., Methods: In this cohort study, patients were recruited as part of a randomised controlled trial done between March 17 and April 28, 2020, that aimed to assess if hydroxychloroquine reduced transmission of SARS-CoV-2. Patients with COVID-19 and their contacts were identified by use of the electronic registry of the Epidemiological Surveillance Emergency Service of Catalonia (Spain). Patients with COVID-19 included in our analysis were aged 18 years or older, not hospitalised, had quantitative PCR results available at baseline, had mild symptom onset within 5 days before enrolment, and had no reported symptoms of SARS-CoV-2 infections in their accommodation or workplace within the 14 days before enrolment. Contacts included were adults with a recent history of exposure and absence of COVID-19-like symptoms within the 7 days preceding enrolment. Viral load of contacts, measured by quantitative PCR from a nasopharyngeal swab, was assessed at enrolment, at day 14, and whenever the participant reported COVID-19-like symptoms. We assessed risk of transmission and developing symptomatic disease and incubation dynamics using regression analysis. We assessed the relationship of viral load and characteristics of cases (age, sex, number of days from reported symptom onset, and presence or absence of fever, cough, dyspnoea, rhinitis, and anosmia) and associations between risk of transmission and characteristics of the index case and contacts., Findings: We identified 314 patients with COVID-19, with 282 (90%) having at least one contact (753 contacts in total), resulting in 282 clusters. 90 (32%) of 282 clusters had at least one transmission event. The secondary attack rate was 17% (125 of 753 contacts), with a variation from 12% when the index case had a viral load lower than 1 × 10 6 copies per mL to 24% when the index case had a viral load of 1 × 10 10 copies per mL or higher (adjusted odds ratio per log 10 increase in viral load 1·3, 95% CI 1·1-1·5). Increased risk of transmission was also associated with household contact (3·0, 1·59-5·65) and age of the contact (per year: 1·02, 1·01-1·04). 449 contacts had a positive PCR result at baseline. 28 (6%) of 449 contacts had symptoms at the first visit. Of 421 contacts who were asymptomatic at the first visit, 181 (43%) developed symptomatic COVID-19, with a variation from approximately 38% in contacts with an initial viral load lower than 1 × 10 7 copies per mL to greater than 66% for those with an initial viral load of 1 × 10 10 copies per mL or higher (hazard ratio per log 10 increase in viral load 1·12, 95% CI 1·05-1·20; p=0·0006). Time to onset of symptomatic disease decreased from a median of 7 days (IQR 5-10) for individuals with an initial viral load lower than 1 × 10 7 copies per mL to 6 days (4-8) for those with an initial viral load between 1 × 10 7 and 1 × 10 9 copies per mL, and 5 days (3-8) for those with an initial viral load higher than 1 × 10 9 copies per mL., Interpretation: In our study, the viral load of index cases was a leading driver of SARS-CoV-2 transmission. The risk of symptomatic COVID-19 was strongly associated with the viral load of contacts at baseline and shortened the incubation time of COVID-19 in a dose-dependent manner., Funding: YoMeCorono, Generalitat de Catalunya., Translations: For the Catalan translation of the abstract see Supplementary Materials section., (Copyright © 2021 Elsevier Ltd. All rights reserved.)