Worsening glycemic control in youth with type 2 diabetes during COVID-19.

Introduction: The COVID-19 pandemic has disproportionately affected minority and lower socioeconomic populations, who also have higher rates of type 2 diabetes (T2D). The impact of virtual school, decreased activity level, and worsening food insecurity on pediatric T2D is unknown. The goal of this study was to evaluate weight trends and glycemic control in youth with existing T2D during the COVID-19 pandemic. Methods: A retrospective study of youth <21 years of age diagnosed with T2D prior to March 11, 2020 was conducted at an academic pediatric diabetes center to compare glycemic control, weight, and BMI in the year prior to the COVID-19 pandemic (March 2019-2020) to during COVID-19 (March 2020-2021). Paired t-tests and linear mixed effects models were used to analyze changes during this period. Results: A total of 63 youth with T2D were included (median age 15.0 (IQR 14-16) years, 59% female, 74.6% black, 14.3% Hispanic, 77.8% with Medicaid insurance). Median duration of diabetes was 0.8 (IQR 0.2-2.0) years. There was no difference in weight or BMI from the pre-COVID-19 period compared to during COVID-19 (Weight: 101.5 v 102.9 kg, p=0.18; BMI: 36.0 v 36.1 kg/m2, p=0.72). Hemoglobin A1c significantly increased during COVID-19 (7.6% vs 8.6%, p=0.0002). Conclusion: While hemoglobin A1c increased significantly in youth with T2D during the COVID-19 pandemic, there was no significant change in weight or BMI possibly due to glucosuria associated with hyperglycemia. Youth with T2D are at high risk for diabetes complications, and the worsening glycemic control in this population highlights the need to prioritize close follow-up and disease management to prevent further metabolic decompensation.

Retrospective, Observational Studies for Estimating Vaccine Effects on the Secondary Attack Rate of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) vaccines are highly efficacious at preventing symptomatic infection, severe disease, and death. Most of the evidence that COVID-19 vaccines also reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is based on retrospective, observational studies. Specifically, an increasing number of studies are evaluating vaccine effectiveness against the secondary attack rate of SARS-CoV-2 using data available in existing health-care databases or contact-tracing databases. Since these types of databases were designed for clinical diagnosis or management of COVID-19, they are limited in their ability to provide accurate information on infection, infection timing, and transmission events. We highlight challenges with using existing databases to identify transmission units and confirm potential SARS-CoV-2 transmission events. We discuss the impact of common diagnostic testing strategies, including event-prompted and infrequent testing, and illustrate their potential biases in estimating vaccine effectiveness against the secondary attack rate of SARS-CoV-2. We articulate the need for prospective observational studies of vaccine effectiveness against the SARS-CoV-2 secondary attack rate, and we provide design and reporting considerations for studies using retrospective databases.

Could widespread use of antiviral treatment curb the COVID-19 pandemic? A modeling study.

BACKGROUND: Despite the development of safe and effective vaccines, effective treatments for COVID-19 disease are still urgently needed. Several antiviral drugs have shown to be effective in reducing progression of COVID-19 disease. METHODS: In the present work, we use an agent-based mathematical model to assess the potential population impact of the use of antiviral treatments in four countries with different demographic structure and current levels of vaccination coverage: Kenya, Mexico, United States (US) and Belgium. We analyzed antiviral effects on reducing hospitalization and death, and potential antiviral effects on reducing transmission. For each country, we varied daily treatment initiation rate (DTIR) and antiviral effect in reducing transmission (AVT). RESULTS: Irrespective of location and AVT, widespread antiviral treatment of symptomatic adult infections (20% DTIR) prevented the majority of COVID-19 deaths, and recruiting 6% of all adult symptomatic infections daily reduced mortality by over 20% in all countries. Furthermore, our model projected that targeting antiviral treatment to the oldest age group (65 years old and older, DTIR of 20%) can prevent over 30% of deaths. Our results suggest that early antiviral treatment (as soon as possible after inception of infection) is needed to mitigate transmission, preventing 50% more infections compared to late treatment (started 3 to 5 days after symptoms onset). Our results highlight the synergistic effect of vaccination and antiviral treatment: as the vaccination rate increases, antivirals have a larger relative impact on population transmission. Finally, our model projects that even in highly vaccinated populations, adding antiviral treatment can be extremely helpful to mitigate COVID-19 deaths. CONCLUSIONS: These results suggest that antiviral treatments can become a strategic tool that, in combination with vaccination, can significantly reduce COVID-19 hospitalizations and deaths and can help control SARS-CoV-2 transmission.

Volunteer advance care planning service pilot

BackgroundAdvance care planning (ACP), with particular reference to care home residents, has been brought to the fore by the COVID-19 pandemic, with concern over residents’ involvement in resuscitation decisions leading to a review by the Care Quality Commission (2021). Whilst recently published Universal Principles (NHS England. 2022) will be helpful, achieving high quality ACP consistently with impact and at scale has proved elusive. In response to this need we piloted an innovative ACP service for capacitous care home residents;delivered remotely by trained volunteers to include treatment escalation plans.AimsTo evaluate our ACP service with reference to: a) concordance between treatment escalation decisions made by residents when supported by a volunteer compared to a GP;b) time taken by volunteers and GPs;c) acceptability of remote ACP in this population;d) feedback on the service from GPs, residents and care home managers.MethodsApr – June 2020: service set up with PCN leads’ support, recruitment and training of volunteers (counsellors and medical students), partial funding from West Yorkshire & Harrogate Health Inequalities Fund. Residents completed an ACP with a volunteer which was then re-discussed with GP. July 2020: Pilot commencement with data collection on time taken, outcomes and feedback questionnaires to all involved. Service evaluation after 25 appropriate referrals.Results95% concordance in escalation plans created with volunteer compared to GP. Average time taken;volunteer 52 mins, GP 12 mins. 100% of residents found the service useful and would recommend to others, with 88% finding the remote platform acceptable. The GPs reported the service as being useful for 96% of referrals.ConclusionAn ACP service for capacitous care home residents delivered remotely by trained volunteers is feasible and acceptable. This has the potential to allow GPs, or clinicians within an ACP service, to reduce down the time taken by building on volunteer-led ACPs or concentrate on complex ACP decisions where clinical input is needed.

Using time-weighted average change from baseline of SARS-CoV-2 viral load to assess impact of hydroxychloroquine as postexposure prophylaxis and early treatment for COVID-19.

Two randomized controlled trials demonstrated no clinical benefit of hydroxychloroquine (HCQ) for either postexposure prophylaxis or early treatment of SARS-CoV-2 infection. Using data from these studies, we calculated the time-weighted average change from baseline SARS-CoV-2 viral load and demonstrated that HCQ did not affect viral clearance.

The Coronavirus Disease 2019 Pandemic is Associated with a Substantial Rise in Frequency and Severity of Presentation of Youth-Onset Type 2 Diabetes.

OBJECTIVES: To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years. STUDY DESIGN: Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups. RESULTS: A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic. CONCLUSIONS: The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

Clinical and survival differences during separate COVID-19 surges: Investigating the impact of the Sars-CoV-2 alpha variant in critical care patients.

A number of studies have highlighted physiological data from the first surge in critically unwell Covid-19 patients but there is a paucity of data describing emerging variants of SARS-CoV-2, such as B.1.1.7. We compared ventilatory parameters, biochemical and physiological data and mortality between the first and second COVID-19 surges in the United Kingdom, where distinct variants of SARS-CoV-2 were the dominant stain. We performed a retrospective cohort study investigating critically unwell patients admitted with COVID-19 across three tertiary regional ICUs in London, UK. Of 1782 adult ICU patients screened, 330 intubated and ventilated patients diagnosed with COVID-19 were included. In the second wave where B.1.1.7 variant was the dominant strain, patients were had increased severity of ARDS whilst compliance was greater (p<0.05) and d-dimer lower. The 28-day mortality was not statistically significant (1st wave: 42.2% vs 2nd wave: 39.8%). However, when adjusted for key covariates, the hazard ratio for 28-day mortality in those patients with B.1.1.7 was 3.79 (CI 1.04-13.8; p = 0.043) compared to the original strain. During the second surge in the UK, where the COVID-19 variant B.1.1.7 was most prevalent, significantly more patients presented to critical care with severe ARDS. Furthermore, mortality risk was significantly greater in our ICU population during the second wave of the pandemic in those patients with B.1.1.7. As ICUs are experiencing further waves (particularly by the delta (B.1.617.2) variant), we highlight the urgent need for prospective studies describing immunological and pathophysiological differences across novel emerging variants.

Rapid decline in vaccine-boosted neutralizing antibodies against SARS-CoV-2 Omicron variant.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits reduced susceptibility to vaccine-induced neutralizing antibodies, requiring a boost to generate protective immunity. We assess the magnitude and short-term durability of neutralizing antibodies after homologous and heterologous boosting with mRNA and Ad26.COV2.S vaccines. All prime-boost combinations substantially increase the neutralization titers to Omicron, although the boosted titers decline rapidly within 2 months from the peak response compared with boosted titers against the prototypic D614G variant. Boosted Omicron neutralization titers are substantially higher for homologous mRNA vaccine boosting, and for heterologous mRNA and Ad26.COV2.S vaccine boosting, compared with homologous Ad26.COV2.S boosting. Homologous mRNA vaccine boosting generates nearly equivalent neutralizing activity against Omicron sublineages BA.1, BA.2, and BA.3 but modestly reduced neutralizing activity against BA.2.12.1 and BA.4/BA.5 compared with BA.1. These results have implications for boosting requirements to protect against Omicron and future variants of SARS-CoV-2. This trial was conducted under ClincalTrials.gov: NCT04889209.

COVID-19 Vaccines and SARS-CoV-2 Transmission in the Era of New Variants: A Review and Perspective.

Coronavirus disease 2019 (COVID-19) vaccines have yielded definitive prevention and major reductions in morbidity and mortality from severe acute respiratory syndrome coronavirus 2 infection, even in the context of emerging and persistent variants of concern. Newer variants have revealed less vaccine protection against infection and attenuation of vaccine effects on transmission. COVID-19 vaccines still likely reduce transmission compared with not being vaccinated at all, even with variants of concern; however, determining the magnitude of transmission reduction is constrained by the challenges of performing these studies, requiring accurate linkage of infections to vaccine status and timing thereof, particularly within households. In this review, we synthesize the currently available data on the impact of COVID-19 vaccines on infection, serious illness, and transmission; we also identify the challenges and opportunities associated with policy development based on this data.

Self-Assessed Severity as a Determinant of Coronavirus Disease 2019 Symptom Specificity: A Longitudinal Cohort Study.

Coronavirus disease 2019 symptom definitions rarely include symptom severity. We collected daily nasal swab samples and symptom diaries from contacts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case patients. Requiring ≥1 moderate or severe symptom reduced sensitivity to predict SARS-CoV-2 shedding from 60.0% (95% confidence interval [CI], 52.9%-66.7%) to 31.5% (95% CI, 25.7%- 38.0%) but increased specificity from 77.5% (95% CI, 75.3%-79.5%) to 93.8% (95% CI, 92.7%-94.8%).

A Mixed Method Study of Teachers' Appraisals of Student Wellness Services and Supports During COVID-19.

BACKGROUND: Understanding teachers' appraisals of student wellness services and supports during COVID-19 is essential to strengthening services and improving student health outcomes. This mixed-method study aimed to examine US PK-12 teachers' appraisals of student wellness services and supports during COVID-19. METHODS: This study focuses on qualitative data from 291 teachers' open-ended responses to the question: "What do you wish your school leaders knew about this (wellness support) aspect of your work?" and whose responses described wellness services and supports. A qualitative content analysis was conducted by an interdisciplinary research team using open- and axial coding. RESULTS: Three main themes emerged. (1) insufficient access to mental health professionals and programming at schools, (2) concern about the quality of available services, and (3) a need for teacher professional development and support on student wellness. Statistically significant differences in teacher appraisals of insufficient access to mental health professionals and programming were found based on grade level taught and percentage of immigrant students in the school. CONCLUSION: With amplified student wellness needs, school personnel, including school leaders, must consider ways to allocate additional resources/staffing, assess the quality of services and supports, and design professional development opportunities to support teachers' involvement in supporting student wellness needs.

Detection and Kinetics of Subgenomic Severe Acute Respiratory Syndrome Coronavirus 2 RNA Viral Load in Longitudinal Diagnostic RNA-Positive Samples.

While detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by diagnostic reverse-transcription polymerase chain reaction (RT-PCR) is highly sensitive for viral RNA, the nucleic acid amplification of subgenomic RNAs (sgRNAs) that are the product of viral replication may more accurately identify replication. We characterized the diagnostic RNA and sgRNA detection by RT-PCR from nasal swab samples collected daily by participants in postexposure prophylaxis or treatment studies for SARS-CoV-2. Among 1932 RT-PCR-positive swab samples with sgRNA tests, 40% (767) had detectable sgRNA. Above a diagnostic RNA viral load (VL) threshold of 5.1 log10 copies/mL, 96% of samples had detectable sgRNA with VLs that followed a linear trend. The trajectories of diagnostic RNA and sgRNA VLs differed, with 80% peaking on the same day but duration of sgRNA detection being shorter (8 vs 14 days). With a large sample of daily swab samples we provide comparative sgRNA kinetics and a diagnostic RNA threshold that correlates with replicating virus independent of symptoms or duration of illness.

Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Acquisition Is Associated With Individual Exposure but Not Community-Level Transmission.

BACKGROUND: Transmission rates after exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive individual within households and healthcare settings varies significantly between studies. Variability in the extent of exposure and community SARS-CoV-2 incidence may contribute to differences in observed rates. METHODS: We examined risk factors for SARS-CoV-2 infection in a randomized controlled trial of hydroxychloroquine as postexposure prophylaxis. Study procedures included standardized questionnaires at enrollment and daily self-collection of midturbinate swabs for SARS-CoV-2 polymerase chain reaction testing. County-level incidence was modeled using federally sourced data. Relative risks and 95% confidence intervals were calculated using modified Poisson regression. RESULTS: Eighty-six of 567 (15.2%) household/social contacts and 12 of 122 (9.8%) healthcare worker contacts acquired SARS-CoV-2 infection. Exposure to 2 suspected index cases (vs 1) significantly increased risk for both household/social contacts (relative risk [RR], 1.86) and healthcare workers (RR, 8.18). Increased contact time also increased risk for healthcare workers (3-12 hours: RR, 7.82, >12 hours: RR, 11.81, vs ≤2 hours), but not for household/social contacts. County incidence did not impact risk. CONCLUSIONS: In our study, increased exposure to SARS-CoV-2 within household or healthcare settings led to higher risk of infection, but elevated community incidence did not. This reinforces the importance of interventions to decrease transmission in close contact settings.

Variants of Concern Are Overrepresented Among Postvaccination Breakthrough Infections of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Washington State.

Across 20 vaccine breakthrough cases detected at our institution, all 20 (100%) infections were due to variants of concern (VOCs) and had a median Ct of 20.2 (IQR, 17.1-23.3). When compared with 5174 contemporaneous samples sequenced in our laboratory, VOCs were significantly enriched among breakthrough infections (P < .05).

Comparison of Racial, Ethnic, and Geographic Location Diversity of Participants Enrolled in Clinic-Based vs 2 Remote COVID-19 Clinical Trials.

Importance: Racial and ethnic diversity among study participants is associated with improved generalizability of clinical trial results and may address inequities in evidence that informs public health strategies. Novel strategies are needed for equitable access and recruitment of diverse clinical trial populations. Objective: To investigate demographic and geographical location data for participants in 2 remote COVID-19 clinical trials with online recruitment and compare with those of a contemporaneous clinic-based COVID-19 study. Design, Setting, and Participants: This cohort study was conducted using data from 3 completed, prospective randomized clinical trials conducted at the same time: 2 remotely conducted studies (the Early Treatment Study and Hydroxychloroquine COVID-19 Postexposure Prophylaxis [PEP] Study) and 1 clinic-based study of convalescent plasma (the Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study). Data were collected from March to August 2020 with 1 to 28 days of participant follow-up. All studies had clinical sites in Seattle, Washington; the 2 remote trials also had collaborating sites in New York, New York; Syracuse, New York; Baltimore, Maryland; Boston, Massachusetts; Chicago, Illinois; New Orleans, Louisiana; and Los Angeles, California. Two remote trials with inclusive social media strategies enrolled 929 participants with recent SARS-CoV-2 exposure (Hydroxychloroquine COVID-19 PEP Trial) and 231 participants with COVID-19 infection (Early Treatment Study); the clinic-based Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study enrolled 250 participants with recent COVID-19 infection. Data were analyzed from April to August 2021. Interventions: Remote trials used inclusive social media strategies and clinician referral for recruitment and telehealth, courier deliveries, and self-collected nasal swabs for remotely conducted study visits. For the clinic-based study, participants were recruited via clinician referral and attended in-person visits. Main Outcomes and Measures: Google Analytics data were used to measure online participant engagement and recruitment. Participant demographics and geographical location data from remote trials were pooled and compared with those of the clinic-based study. Statistical comparison of demographic data was limited to participants with COVID infections (ie, those in the remotely conducted Early Treatment Study vs those in the clinic-based study) to improve accuracy of comparison given that the Hydroxychloroquine COVID-19 PEP Trial enrolled participants with COVID-19 exposures and thus had different enrollment criteria. Results: A total of 1410 participants were included. Among 1160 participants in remote trials and 250 participants in the clinic-based trial, the mean (range) age of participants was 39 (18-80) years vs 50 (19-79) years and 676 individuals (58.3%) vs 131 individuals (52.4%) reported female sex. The Early Treatment Study with inclusive social media strategies enrolled 231 participants in 41 US states with increased rates of racial, ethnic, and geographic diversity compared with participants in the clinic-based study. Among 228 participants in the remotely conducted Early Treatment Study with race data vs participants in the clinic-based study, 39 individuals (17.1%) vs 1 individual (0.4%) identified as Alaska Native or American Indian, 11 individuals (4.8%) vs 22 individuals (8.8%) identified as Asian, 26 individuals (11.4%) vs 4 individuals (1.6%) identified as Black, 3 individuals (1.3%) vs 1 individual identified as Native Hawaiian or Pacific Islander, 117 individuals (51.3%) vs 214 individuals (85.6%) identified as White, and 32 individuals (14.0%) vs 8 individuals (3.2%) identified as other race (P < .001). Among 230 individuals in the Early Treatment Study vs 236 individuals in the clinic-based trial with ethnicity data, 71 individuals (30.9%) vs 11 individuals (4.7%) identified as Hispanic or Latinx (P<.001). There were 29 individuals in the Early Treatment Study with nonurban residences (ie, rural, small town, or peri-urban; 12.6%) vs 6 of 248 individuals in the clinic-based trial with residence data (2.4%) (P < .001). In remote trial online recruitment, the highest engagement was with advertisements on social media platforms; among 125 147 unique users with age demographics who clicked on online recruitment advertisements, 84 188 individuals (67.3%) engaged via Facebook. Conclusions and Relevance: These findings suggest that remote clinical trials with online advertising may be considered as a strategy to improve diversity among clinical trial participants.

Homologous and Heterologous Covid-19 Booster Vaccinations.

BACKGROUND: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. METHODS: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 µg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 µg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. RESULTS: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. CONCLUSIONS: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).

Trajectory of Viral RNA Load Among Persons With Incident SARS-CoV-2 G614 Infection (Wuhan Strain) in Association With COVID-19 Symptom Onset and Severity.

Importance: The SARS-CoV-2 viral trajectory has not been well characterized in incident infections. These data are needed to inform natural history, prevention practices, and therapeutic development. Objective: To characterize early SARS-CoV-2 viral RNA load (hereafter referred to as viral load) in individuals with incident infections in association with COVID-19 symptom onset and severity. Design, Setting, and Participants: This prospective cohort study was a secondary data analysis of a remotely conducted study that enrolled 829 asymptomatic community-based participants recently exposed (<96 hours) to persons with SARS-CoV-2 from 41 US states from March 31 to August 21, 2020. Two cohorts were studied: (1) participants who were SARS-CoV-2 negative at baseline and tested positive during study follow-up, and (2) participants who had 2 or more positive swabs during follow-up, regardless of the initial (baseline) swab result. Participants collected daily midturbinate swab samples for SARS-CoV-2 RNA detection and maintained symptom diaries for 14 days. Exposure: Laboratory-confirmed SARS-CoV-2 infection. Main Outcomes and Measures: The observed SARS-CoV-2 viral load among incident infections was summarized, and piecewise linear mixed-effects models were used to estimate the characteristics of viral trajectories in association with COVID-19 symptom onset and severity. Results: A total of 97 participants (55 women [57%]; median age, 37 years [IQR, 27-52 years]) developed incident infections during follow-up. Forty-two participants (43%) had viral shedding for 1 day (median peak viral load cycle threshold [Ct] value, 38.5 [95% CI, 38.3-39.0]), 18 (19%) for 2 to 6 days (median Ct value, 36.7 [95% CI, 30.2-38.1]), and 31 (32%) for 7 days or more (median Ct value, 18.3 [95% CI, 17.4-22.0]). The cycle threshold value has an inverse association with viral load. Six participants (6%) had 1 to 6 days of viral shedding with censored duration. The peak mean (SD) viral load was observed on day 3 of shedding (Ct value, 33.8 [95% CI, 31.9-35.6]). Based on the statistical models fitted to 129 participants (60 men [47%]; median age, 38 years [IQR, 25-54 years]) with 2 or more SARS-CoV-2-positive swab samples, persons reporting moderate or severe symptoms tended to have a higher peak mean viral load than those who were asymptomatic (Ct value, 23.3 [95% CI, 22.6-24.0] vs 30.7 [95% CI, 29.8-31.4]). Mild symptoms generally started within 1 day of peak viral load, and moderate or severe symptoms 2 days after peak viral load. All 535 sequenced samples detected the G614 variant (Wuhan strain). Conclusions and Relevance: This cohort study suggests that having incident SARS-CoV-2 G614 infection was associated with a rapid viral load peak followed by slower decay. COVID-19 symptom onset generally coincided with peak viral load, which correlated positively with symptom severity. This longitudinal evaluation of the SARS-CoV-2 G614 with frequent molecular testing serves as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.

Mathematical Modeling of Vaccines That Prevent SARS-CoV-2 Transmission.

SARS-CoV-2 vaccine clinical trials assess efficacy against disease (VEDIS), the ability to block symptomatic COVID-19. They only partially discriminate whether VEDIS is mediated by preventing infection completely, which is defined as detection of virus in the airways (VESUSC), or by preventing symptoms despite infection (VESYMP). Vaccine efficacy against transmissibility given infection (VEINF), the decrease in secondary transmissions from infected vaccine recipients, is also not measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna (mRNA-1273QS) and Pfizer-BioNTech (BNT162b2) vaccines, which demonstrated VEDIS > 90% in clinical trials, mediate VEDIS by VESUSC, then a limited fourth epidemic wave of infections with the highly infectious B.1.1.7 variant would have been predicted in spring 2021 assuming rapid vaccine roll out. If high VEDIS is explained by VESYMP, then high VEINF would have also been necessary to limit the extent of this fourth wave. Vaccines which completely protect against infection or secondary transmission also substantially lower the number of people who must be vaccinated before the herd immunity threshold is reached. The limited extent of the fourth wave suggests that the vaccines have either high VESUSC or both high VESYMP and high VEINF against B.1.1.7. Finally, using a separate intra-host mathematical model of viral kinetics, we demonstrate that a 0.6 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve 50% VEINF, which suggests that human challenge studies with a relatively low number of infected participants could be employed to estimate all three vaccine efficacy metrics.