Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age.

BACKGROUND: Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children. METHODS: We conducted a phase 1 dose-finding study and are conducting an ongoing phase 2-3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2-3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-µg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-µg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 µg of BNT162b2 in the pivotal trial. RESULTS: During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-µg dose) and 48 children 2 to 4 years of age (3-µg or 10-µg dose). The 3-µg dose level was selected for the phase 2-3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases). CONCLUSIONS: A three-dose primary series of 3-µg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference.

Background: The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference. Methods: We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage. Results: Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0-40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17-208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02-1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28-.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23-1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants. Conclusions: Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation.

Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries. METHODS: We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis. RESULTS: We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48-1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54-1.29]; sustained: HR, 0.87 [95% CI, .52-1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. CONCLUSIONS: Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04346628.

Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study.

Background: The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients. Methods: Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial. Results: We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset. Conclusions: Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models. Funding: Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.

Gender Differences in National Institutes of Health Grant Submissions Before and During the COVID-19 Pandemic.

Introduction: Emerging data suggest that the COVID-19 pandemic has disproportionately impacted women in academic medicine, potentially eliminating recent gains that have been made toward gender equity. This study examined possible pandemic-related gender disparities in research grant submissions, one of the most important criteria for academic promotion and tenure evaluations. Methods: Data were collected from two major academic institutions (one private and one public) on the gender and academic rank of faculty principal investigators who submitted new grants to the National Institutes of Health (NIH) during COVID-19 (March 1st, 2020, through August 31, 2020) compared with a matched period in 2019 (March 1st, 2019, through August 31, 2019). t-Tests and chi-square analyses compared the gender distribution of individuals who submitted grants during the two periods of examination. Results: In 2019 (prepandemic), there was no significant difference in the average number of grants submitted by women compared with men faculty. In contrast, women faculty submitted significantly fewer grants in 2020 (during the pandemic) than men. Men were also significantly more likely than women to submit grants in both 2019 and 2020 compared with submitting in 2019 only, suggesting men faculty may have been more likely than their women colleagues to sustain their productivity in grant submissions during the pandemic. Discussion: Women's loss of extramural funding may compound over time, as it impedes new data collection, research progress, and academic advancement. Efforts to support women's research productivity and career trajectories are urgently needed in the following years of pandemic recovery.

Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries. METHODS: We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis. RESULTS: We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48-1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54-1.29]; sustained: HR, 0.87 [95% CI, .52-1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. CONCLUSIONS: Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04346628.

Feasibility of Specimen Self-collection in Young Children Undergoing SARS-CoV-2 Surveillance for In-Person Learning.

Importance: There is an urgent need to assess the feasibility of COVID-19 surveillance measures in educational settings. Objective: To assess whether young children can feasibly self-collect SARS-CoV-2 samples for surveillance testing over the course of an academic year. Design, Setting, and Participants: This prospective pilot cohort study was conducted from September 10, 2020, to June 10, 2021, at a K-8 school in San Mateo County, California. The research consisted of quantitative data collection efforts: (1) demographic data collected, (2) student sample self-collection error rates, and (3) student sample self-collection time durations. Students were enrolled in a hybrid learning model, a teaching model in which students were taught in person and online, with students having the option to attend virtually as needed. Data were collected under waiver of consent from students participating in weekly SARS-CoV-2 testing. Main Outcomes and Measures: Errors over time for self-collection of nasal swabs such as contaminated swabs and inadequate or shallow swabbing; time taken for sample collection. Results: Of 296 participants, 148 (50.0%) were boys and 148 (50.0%) were girls. A total of 87 participants (29.2%) identified as Asian; 2 (0.6%), Black or African American; 13 (4.4%), Hispanic/Latinx; 103 (34.6%), non-Hispanic White; 87 (29.2%), multiracial; and 6 (2.0%), other. The median school grade was fourth grade. From September 2020 to March 2021, a total of 4203 samples were obtained from 221 students on a weekly basis, while data on error rates were collected. Errors occurred in 2.7% (n = 107; 95% CI, 2.2%-3.2%) of student encounters, with the highest rate occurring on the first day of testing (20 [10.2%]). There was an overall decrease in error rates over time. From April to June 2021, a total of 2021 samples were obtained from 296 students on a weekly basis while data on encounter lengths were collected. Between April and June 2021, 193 encounters were timed. The mean duration of each encounter was 70 seconds (95% CI, 66.4-73.7 seconds). Conclusions and Relevance: Mastery of self-collected lower nasal swabs is possible for children 5 years and older. Testing duration can be condensed once students gain proficiency in testing procedures. Scalability for larger schools is possible if consideration is given to the resource-intensive nature of the testing and the setting's weather patterns.

Everyday Heroism: Maintaining Organizational Cultures of Wellness and Inclusive Excellence Amid Simultaneous Pandemics.

Health care professionals and the institutions in which they work are being stretched to their limits amidst the current COVID-19 pandemic. At the same time, a second longstanding pandemic has been brought to the fore: the entrenched system of racial injustice and oppression. The first pandemic is new, and to date, substantial resources have been allocated to urgently addressing its mitigation; the second has a long history with inconsistent attention and resources but has recently been spotlighted more intensely than at any time in the nation's recent past. The authors contend that these 2 simultaneous pandemics have brought forth the need for institutions in the United States to make a renewed commitment to respect, wellness, diversity, and inclusion. While investment and leadership in these domains have always been essential, these have largely been viewed as a "nice-to-have" option. The events of much of 2020 (most notably) have illustrated that committing to and investing in policies, programs, centers, and leadership to drive change in these domains are essential and a "need-to-have" measure. The authors outline the necessity of investing in the promotion of cultures of inclusive excellence at both individual and organizational levels to coordinate a united response to the simultaneous pandemics. It is in the interests of health care systems to consider the wellness of the workforce to overcome the longer-term economic, systemic, and social trauma that will likely occur for years to come at both the individual and institutional levels. Maintaining or augmenting investment is necessary despite the economic challenges the nation faces. Now is the time to cultivate resilience and wellness through a renewed commitment to cultures of respect, diversity, and inclusion. This commitment is urgently needed to support and sustain the health care workforce and maintain outstanding health care systems for future generations.

Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) seroprevalence in healthcare personnel in northern California early in the coronavirus disease 2019 (COVID-19) pandemic.

OBJECTIVE: We assessed the magnitude of unidentified coronavirus disease 2019 (COVID-19) in our healthcare personnel (HCP) early in the COVID-19 pandemic, and we evaluated risk factors for infection to identify areas for improvement in infection control practice in a northern California academic medical center. METHODS: We reviewed anti-severe acute respiratory coronavirus virus 2 (SARS-CoV-2) receptor-binding domain (RBD) IgG serologic test results and self-reported risk factors for seropositivity among 10,449 asymptomatic HCP who underwent voluntary serology testing between April 20 and May 20, 2020. RESULTS: In total, 136 employees (1.3%) tested positive for SARS-CoV-2 IgG. This included 41 individuals (30.1%) who had previously tested positive for SARS-CoV-2 by nasopharyngeal reverse-transcription polymerase chain reaction (RT-PCR) between March 13 and April 16, 2020. In multivariable analysis, employees of Hispanic ethnicity (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.22-3.46) and those working in environmental services, food services, or patient transport (OR, 4.81; 95% CI, 2.08-10.30) were at increased risk for seropositivity compared to other groups. Employees reporting a household contact with COVID-19 were also at higher risk for seropositivity (OR, 3.25; 95% CI, 1.47-6.44), but those with a work, exposure alone were not (OR, 1.27; 95% CI, 0.58-2.47). Importantly, one-third of seropositive individuals reported no prior symptoms, no suspected exposures, and no prior positive RT-PCR test. CONCLUSION: In this study, SARS-CoV-2 seropositivity among HCP early in the northern California epidemic appeared to be quite low and was more likely attributable to community rather than occupational exposure.

Update From the Advisory Committee on Immunization Practices.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts, normally meets 3 times per year to develop recommendations for vaccine use in the United States. Because of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) pandemic, there are several SARS-CoV-2 vaccines currently in late-stage clinical trials, so the ACIP is now meeting monthly for single day meetings, with plans to continue standard 2- to 3-day meetings as per usual (February, June, and October). Emergency meetings of ACIP may occur if a vaccine candidate receives an Emergency Use Authorization from the food and drug administration (FDA). This Update provides a combined summary of the August 26 and September 22, 2020, meetings, both of which focused completely on Coronavirus disease 2019 (COVID-19) vaccines. The representatives from the American Academy of Pediatrics (Y. A. M. and D. W. K.) and the Pediatric Infectious Diseases Society (S. T. O.) are present as liaisons to the ACIP.

Kinetics of SARS-CoV-2 positivity of infected and recovered patients from a single center.

Recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive detection in infected but recovered individuals has been reported. Patients who have recovered from coronavirus disease 2019 (COVID-19) could profoundly impact the health care system. We sought to define the kinetics and relevance of PCR-positive recurrence during recovery from acute COVID-19 to better understand risks for prolonged infectivity and reinfection. A series of 414 patients with confirmed SARS-Cov-2 infection, at The Second Affiliated Hospital of Southern University of Science and Technology in Shenzhen, China from January 11 to April 23, 2020. Statistical analyses were performed of the clinical, laboratory, radiologic image, medical treatment, and clinical course of admission/quarantine/readmission data, and a recurrence predictive algorithm was developed. 16.7% recovered patients with PCR positive recurring one to three times, despite being in strict quarantine. Younger patients with mild pulmonary respiratory syndrome had higher risk of PCR positivity recurrence. The recurrence prediction model had an area under the ROC curve of 0.786. This case series provides characteristics of patients with recurrent SARS-CoV-2 positivity. Use of a prediction algorithm may identify patients at high risk of recurrent SARS-CoV-2 positivity and help to establish protocols for health policy.