Cross-neutralizing antibody against emerging Omicron subvariants of SARS-CoV-2 in infection-naïve individuals with homologous BNT162b2 or BNT162b2(WT+ BA.4/5) bivalent booster vaccination (preprint)

Since the emergence of SARS-CoV-2, different variants and subvariants successively emerged to dominate global virus circulation as a result of immune evasion, replication fitness or both. COVID-19 vaccines continue to be updated in response to the emergence of antigenically divergent viruses, the first being the bivalent RNA vaccines that encodes for both the Wuhan-like and Omicron BA.5 subvariant spike proteins. Repeated infections and vaccine breakthrough infections have led to complex immune landscapes in populations making it increasingly difficult to assess the intrinsic neutralizing antibody responses elicited by the vaccines. Hong Kong’s intensive COVID-19 containment policy through 2020–2021 permitted us to identify sera from a small number of infection naïve individuals who received 3 doses RNA vaccine BNT162b2 of vaccines encoding the Wuhan-like spike who were boosted with a fourth dose monovalent Wuhan-like (WT) vaccine or the bivalent Wuhan-like and BA.4/5 spike (WT + BA.4/5) expressing vaccine. While neutralizing antibody to wild-type virus was comparable in both vaccine groups, BNT162b2 bivalent vaccine elicited significantly higher plaque neutralizing antibodies to Omicron subvariants BA.5, XBB.1.5, XBB.1.16, XBB.1.9.1, XBB.2.3.2, EG.5.1, HK.3, BA.2.86 and JN.1, compared to BNT162b2 monovalent vaccine. The single amino acid substitution that differentiates the spike of JN.1 from BA.2.86 resulted in a profound antigenic change.

Durability of protection from original monovalent and bivalent COVID-19 vaccines against COVID-19-associated hospitalization and severe in-hospital outcomes among adults in the United States -- September 2022-August 2023 (preprint)

ObjectiveTo evaluate the durability of protection provided by original monovalent and bivalent COVID-19 vaccination against COVID-19-associated hospitalization and severe in-hospital outcomes. DesignMulticenter case-control design with prospective enrollment Setting26 hospitals in 20 US states ParticipantsAdults aged [≥]18 years admitted to hospital with COVID-19-like illness from 8 September 2022 to 31 August 2023 Main outcome measuresThe main outcomes were absolute and relative vaccine effectiveness of original monovalent and bivalent COVID-19 vaccines against COVID-19-associated hospitalization and severe in-hospital outcomes, including advanced respiratory support (defined as receipt of high-flow nasal cannula, non-invasive ventilation, or invasive mechanical ventilation [IMV]) and IMV or death. Vaccine effectiveness was estimated using multivariable logistic regression, in which the odds of vaccination (versus being unvaccinated or receiving original monovalent vaccination only) were compared between COVID-19 case patients and control-patients. Bivalent vaccine effectiveness analyses were stratified by time since dose receipt. ResultsAmong 7028 adults without immunocompromising conditions, 2924 (41.6%) were COVID-19 case patients and 4104 (58.4%) were control patients. Compared to unvaccinated patients, absolute vaccine effectiveness against COVID-19-associated hospitalization was 6% (-7% to 17%) for original monovalent doses only (median time since last dose [IQR] = 421 days [304-571]), 52% (39% to 61%) for a bivalent dose received 7-89 days earlier, and 13% (-10% to 31%) for a bivalent dose received 90-179 days earlier. Absolute vaccine effectiveness against COVID-19-associated advanced respiratory support was 31% (15% to 45%) for original monovalent doses only, 66% (47% to 78%) for a bivalent dose received 7-89 days earlier, and 33% (-1% to 55%) for a bivalent dose received 90-179 days earlier. Absolute vaccine effectiveness against COVID-19-associated IMV or death was 51% (34% to 63%) for original monovalent doses only, 61% (35% to 77%) for a bivalent dose received 7-89 days earlier, and 50% (11% to 71%) for a bivalent dose received 90-179 days earlier. ConclusionWhen compared to original monovalent vaccination only, bivalent COVID-19 vaccination provided additional protection against COVID-19-associated hospitalization and certain severe in-hospital outcomes within 3 months of dose receipt. By 3-6 months, protection from a bivalent dose declined to a level similar to that remaining from original monovalent vaccination only. Although no protection remained from original monovalent vaccination against COVID-19-associated hospitalization, it provided durable protection against severe in-hospital outcomes >1 year after receipt of the last dose, particularly against IMV or death. SUMMARY BOX What is already known on this topic- On September 1, 2022, bivalent mRNA COVID-19 vaccination was recommended for US adults who had completed at least an original monovalent COVID-19 primary series. - Early estimates of bivalent vaccine effectiveness are available for the period soon after dose receipt; however fewer data exist on their durability of protection and effectiveness against severe outcomes. What this study adds- When compared to original monovalent vaccination only, bivalent mRNA COVID-19 vaccination provided additional protection against COVID-19-associated hospitalization and certain severe in-hospital outcomes within 3 months of dose receipt. By 3-6 months, protection from a bivalent dose declined to a level similar to that remaining from original monovalent vaccination only. - Although no protection remained from original monovalent vaccination against COVID-19-associated hospitalization, it provided durable protection against severe in-hospital outcomes >1 year after receipt of the last dose, particularly against invasive mechanical ventilation or death.

Dynamic Contact Networks of Residents of an Urban Jail in the Era of SARS-CoV-2 (preprint)

BACKGROUND. In custodial settings such as jails and prisons, infectious disease transmission is heightened by factors such as overcrowding and limited healthcare access. Specific features of social contact networks within these settings have not been sufficiently characterized, especially in the context of a large-scale respiratory infectious disease outbreak. The study aims to quantify contact network dynamics within the Fulton County Jail in Atlanta, Georgia, to improve our understanding respiratory disease spread to informs public health interventions. METHODS. As part of the Surveillance by Wastewater and Nasal Self-collection of Specimens (SWANSS) study, jail roster data were utilized to construct social contact networks. Rosters included resident details, cell locations, and demographic information. This analysis involved 6,702 residents over 140,901 person days. Network statistics, including degree, mixing, and turnover rates, were assessed across age groups, race/ethnicities, and jail floors. We compared outcomes for two distinct periods (January 2022 and April 2022) to understand potential responses in network structures during and after the SARS-CoV-2 Omicron variant peak. RESULTS. We found high cross-sectional network degree at both cell and block levels, indicative of substantial daily contacts. While mean degree increased with age, older residents exhibited lower degree during the Omicron peak, suggesting potential quarantine measures. Block-level networks demonstrated higher mean degrees than cell-level networks. Cumulative degree distributions for both levels increased from January to April, indicating heightened contacts after the outbreak. Assortative age mixing was strong, especially for residents aged 20-29. Dynamic network statistics illustrated increased degrees over time, emphasizing the potential for disease spread, albeit with a lower growth rate during the Omicron peak. CONCLUSIONS. The contact networks within the Fulton County Jail presented ideal conditions for infectious disease transmission. Despite some reduction in network characteristics during the Omicron peak, the potential for disease spread remained high. Age-specific mixing patterns suggested unintentional age segregation, potentially limiting disease spread to older residents. The study underscores the need for ongoing monitoring of contact networks in carceral settings and provides valuable insights for epidemic modeling and intervention strategies, including quarantine, depopulation, and vaccination. This network analysis offers a foundation for understanding disease dynamics in carceral environments.

Can long-term COVID-19 vaccination be improved by serological surveillance?: a modeling study for Mozambique (preprint)

Seroprevalence provides an estimate of the population-level susceptibility to infection. In this study, we used a transmission model to examine the potential of using serological surveillance to inform the timing of COVID-19 boosters in Mozambique. We simulated using population-level seroprevalence thresholds as an estimate of the risk of outbreaks to trigger the timing of re-vaccination campaigns among older adults. We compare this approach to a strategy of re-vaccination at fixed time intervals. Vaccinating older adults each time the seroprevalence among older adults falls below 50% and 80% resulted in medians of 20% and 71% reduction in deaths, respectively, and number-needed-to-vaccinate to avert one death (NNT) of 1,499 (2.5th-97.5th centile:1,252-1,905) and 3,151 (2,943-3,429), respectively. In comparison, biennial and annual re-vaccination of older adults resulted in medians of 35% and 52% deaths averted, respectively, and NNTs of 1,443 (1,223-1,733) and 1,941 (1,805-2,112), respectively. We conducted sensitivity analysis over a range of antibody waning rates and epidemic scenarios and found that re-vaccination trigger thresholds of 50-60% seroprevalence are most likely to be efficient compared to fixed-time strategies. However, given marginal gains in efficiency even in the best-case scenarios, our results favor the use of simpler fixed-time strategies for long-term control of SARS-CoV-2.

Modelling the Interplay between Responsive Individual Vaccination Decisions and the Spread of SARS-CoV-2 (preprint)

The uptake of COVID-19 vaccines remains low despite their high effectiveness. Epidemic models that represent decision-making psychology can provide insight into the potential impact of vaccine promotion interventions in the context of the COVID-19 pandemic. We coupled a network-based mathematical model of SARS-CoV-2 transmission in Georgia, USA with a social-psychological vaccination decision-making model in which vaccine side effects, post-vaccination infections, and other unidentified community-level factors could "nudge" individuals towards vaccine resistance while hospitalization spikes could nudge them towards willingness. Combining an increased probability of hospitalization-prompted resistant-to-willing switches with a decreased probability of willing-to-resistant switches prompted by unidentified community-level factors increased vaccine uptake and decreased SARS-CoV-2 incidence by as much as 30.7% and 24.0%, respectively. The latter probability had a greater impact than the former. This illustrates the disease prevention potential of vaccine promotion interventions that address community-level factors influencing decision-making and anticipate the case curve instead of reacting to it.

Changing Severity and Epidemiology of Adults Hospitalized With Coronavirus Disease 2019 (COVID-19) in the United States After Introduction of COVID-19 Vaccines, March 2021-August 2022.

INTRODUCTION: Understanding the changing epidemiology of adults hospitalized with coronavirus disease 2019 (COVID-19) informs research priorities and public health policies. METHODS: Among adults (≥18 years) hospitalized with laboratory-confirmed, acute COVID-19 between 11 March 2021, and 31 August 2022 at 21 hospitals in 18 states, those hospitalized during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-predominant period (BA.1, BA.2, BA.4/BA.5) were compared to those from earlier Alpha- and Delta-predominant periods. Demographic characteristics, biomarkers within 24 hours of admission, and outcomes, including oxygen support and death, were assessed. RESULTS: Among 9825 patients, median (interquartile range [IQR]) age was 60 years (47-72), 47% were women, and 21% non-Hispanic Black. From the Alpha-predominant period (Mar-Jul 2021; N = 1312) to the Omicron BA.4/BA.5 sublineage-predominant period (Jun-Aug 2022; N = 1307): the percentage of patients who had ≥4 categories of underlying medical conditions increased from 11% to 21%; those vaccinated with at least a primary COVID-19 vaccine series increased from 7% to 67%; those ≥75 years old increased from 11% to 33%; those who did not receive any supplemental oxygen increased from 18% to 42%. Median (IQR) highest C-reactive protein and D-dimer concentration decreased from 42.0 mg/L (9.9-122.0) to 11.5 mg/L (2.7-42.8) and 3.1 mcg/mL (0.8-640.0) to 1.0 mcg/mL (0.5-2.2), respectively. In-hospital death peaked at 12% in the Delta-predominant period and declined to 4% during the BA.4/BA.5-predominant period. CONCLUSIONS: Compared to adults hospitalized during early COVID-19 variant periods, those hospitalized during Omicron-variant COVID-19 were older, had multiple co-morbidities, were more likely to be vaccinated, and less likely to experience severe respiratory disease, systemic inflammation, coagulopathy, and death.

The Maryland (USA) Critical Care Coordination Center (C4): From Pandemic to Permanence.

INTRODUCTION: The 2019 coronavirus disease (COVID-19) pandemic created overwhelming demand for critical care services within Maryland's (USA) hospital systems. As intensive care units (ICUs) became full, critically ill patients were boarded in hospital emergency departments (EDs), a practice associated with increased mortality and costs. Allocation of critical care resources during the pandemic requires thoughtful and proactive management strategies. While various methodologies exist for addressing the issue of ED overcrowding, few systems have implemented a state-wide response using a public safety-based platform. The objective of this report is to describe the implementation of a state-wide Emergency Medical Services (EMS)-based coordination center designed to ensure timely and equitable access to critical care. METHODS: The state of Maryland designed and implemented a novel, state-wide Critical Care Coordination Center (C4) staffed with intensivist physicians and paramedics purposed to ensure appropriate critical care resource management and patient transfer assistance. A narrative description of the C4 is provided. A retrospective cohort study design was used to present requests to the C4 as a case series report to describe the results of implementation. RESULTS: Providing a centralized asset with regional situational awareness of hospital capability and bed status played an integral role for directing the triage process of critically ill patients to appropriate facilities during and after the COVID-19 pandemic. A total of 2,790 requests were received by the C4. The pairing of a paramedic with an intensivist physician resulted in the successful transfer of 67.4% of requests, while 27.8% were managed in place with medical direction. Overall, COVID-19 patients comprised 29.5% of the cohort. Data suggested increased C4 usage was predictive of state-wide ICU surges. The C4 usage volume resulted in the expansion to pediatric services to serve a broader age range. The C4 concept, which leverages the complimentary skills of EMS clinicians and intensivist physicians, is presented as a proposed public safety-based model for other regions to consider world-wide. CONCLUSION: The C4 has played an integral role in the State of Maryland's pledge to its citizens to deliver the right care to the right patient at the right time and can be considered as a model for adoption by other regions world-wide.

Achieving the "Ending the HIV Epidemic in the U.S." incidence reduction goals among at-risk populations in the South.

INTRODUCTION: Antiretroviral medication coverage remains sub-optimal in much of the United States, particularly the Sothern region, and Non-Hispanic Black or African American persons (NHB) continue to be disproportionately impacted by the HIV epidemic. The "Ending the HIV Epidemic in the U.S." (EHE) initiative seeks to reduce HIV incidence nationally by focusing resources towards the most highly impacted localities and populations. This study evaluates the impact of hypothetical improvements in ART and PrEP coverage to estimate the levels of coverage needed to achieve EHE goals in the South. METHODS: We developed a stochastic, agent-based network model of 500,000 individuals to simulate the HIV epidemic and hypothetical improvements in ART and PrEP coverage. RESULTS: New infections declined by 78.6% at 90%/40% ART/PrEP and 94.3% at 100%/50% ART/PrEP. Declines in annual incidence rates surpassed 75% by 2025 with 90%/40% ART/PrEP and 90% by 2030 with 100%/50% ART/PrEP coverage. Increased ART coverage among NHB MSM was associated with a linear decline in incidence among all MSM. Declines in incidence among Hispanic/Latino and White/Other MSM were similar regardless of which MSM race group increased their ART coverage, while the benefit to NHB MSM was greatest when their own ART coverage increased. The incidence rate among NHB women declined by over a third when either NHB heterosexual men or NHB MSM increased their ART use respectively. Increased use of PrEP was associated with a decline in incidence for the groups using PrEP. MSM experienced the largest absolute declines in incidence with increasing PrEP coverage, followed by NHB women. CONCLUSIONS: Our analysis indicates that it is possible to reach EHE goals. The largest reductions in HIV incidence can be achieved by increasing ART coverage among MSM and all race groups benefit regardless of differences in ART initiation by race. Improving ART coverage to > 90% should be prioritized with a particular emphasis on reaching NHB MSM. Such a focus will reduce the largest number of incident cases, reduce racial HIV incidence disparities among both MSM and women, and reduce racial health disparities among persons with HIV. NHB women should also be prioritized for PrEP outreach.

Trends of Autologous Free-Flap Breast Reconstruction and Safety during the Coronavirus Disease 2019 Pandemic.

BACKGROUND: Autologous free-flap breast reconstruction (ABR) is a valuable surgical option for patients following mastectomy. The coronavirus disease 2019 (COVID-19) pandemic has led to a myriad of factors that have affected access to care, hospital logistics, and postoperative outcomes. This study aims to identify differences in patient selection, hospital course and severity, and postoperative outcomes for patients who underwent ABR during and prior to the COVID-19 pandemic. METHODS: Patients undergoing ABR from the American College of Surgeons National Surgical Quality Improvement Program 2019 to 2020 database were analyzed to compare sociodemographics, hospital course, and outcomes over the first postoperative month. Multivariable logistic regression was used to identify factors predictive of complications based on the operative year. RESULTS: In total, 3,770 breast free flaps were stratified into two groups based on the timing of reconstruction (prepandemic and pandemic groups). Patients with a diagnosis of disseminated cancer were significantly less likely to undergo ABR during the COVID-19 pandemic. On univariate analysis, there were no significant differences in postoperative complications between the two groups. When controlling for potentially confounding sociodemographic and clinical risk factors, the COVID-19 group was significantly more likely to undergo reoperation compared with the prepandemic group (p < 0.05). CONCLUSION: When comparing outcomes for patients who underwent ABR prior to and during the COVID-19 pandemic, we found a significant increase in the odds of reoperation for those who had ABR during the pandemic. Debridement procedures and exploration for postoperative hemorrhage, thrombosis, or infection increased in the prepandemic group compared to the COVID-19 group. Notably, operative times decreased.

Antibody and T cell responses against wild-type and Omicron SARS-CoV-2 after third-dose BNT162b2 in adolescents.

The high effectiveness of the third dose of BNT162b2 in healthy adolescents against Omicron BA.1 has been reported in some studies, but immune responses conferring this protection are not yet elucidated. In this analysis, our study (NCT04800133) aims to evaluate the humoral and cellular responses against wild-type and Omicron (BA.1, BA.2 and/or BA.5) SARS-CoV-2 before and after a third dose of BNT162b2 in healthy adolescents. At 5 months after 2 doses, S IgG, S IgG Fc receptor-binding, and neutralising antibody responses waned significantly, yet neutralising antibodies remained detectable in all tested adolescents and S IgG avidity increased from 1 month after 2 doses. The antibody responses and S-specific IFN-γ+ and IL-2+ CD8+ T cell responses were significantly boosted in healthy adolescents after a homologous third dose of BNT162b2. Compared to adults, humoral responses for the third dose were non-inferior or superior in adolescents. The S-specific IFN-γ+ and IL-2+ CD4+ and CD8+ T cell responses in adolescents and adults were comparable or non-inferior. Interestingly, after 3 doses, adolescents had preserved S IgG, S IgG avidity, S IgG FcγRIIIa-binding, against Omicron BA.2, as well as preserved cellular responses against BA.1 S and moderate neutralisation levels against BA.1, BA.2 and BA.5. Sera from 100 and 96% of adolescents tested at 1 and 5 months after two doses could also neutralise BA.1. Our study found high antibody and T cell responses, including potent cross-variant reactivity, after three doses of BNT162b2 vaccine in adolescents in its current formulation, suggesting that current vaccines can be protective against symptomatic Omicron disease.

Comparison of mRNA vaccine effectiveness against COVID-19-associated hospitalization by vaccination source: Immunization information systems, electronic medical records, and self-report-IVY Network, February 1-August 31, 2022.

BACKGROUND: Accurate determination of COVID-19 vaccination status is necessary to produce reliable COVID-19 vaccine effectiveness (VE) estimates. Data comparing differences in COVID-19 VE by vaccination sources (i.e., immunization information systems [IIS], electronic medical records [EMR], and self-report) are limited. We compared the number of mRNA COVID-19 vaccine doses identified by each of these sources to assess agreement as well as differences in VE estimates using vaccination data from each individual source and vaccination data adjudicated from all sources combined. METHODS: Adults aged ≥18 years who were hospitalized with COVID-like illness at 21 hospitals in 18 U.S. states participating in the IVY Network during February 1-August 31, 2022, were enrolled. Numbers of COVID-19 vaccine doses identified by IIS, EMR, and self-report were compared in kappa agreement analyses. Effectiveness of mRNA COVID-19 vaccines against COVID-19-associated hospitalization was estimated using multivariable logistic regression models to compare the odds of COVID-19 vaccination between SARS-CoV-2-positive case-patients and SARS-CoV-2-negative control-patients. VE was estimated using each source of vaccination data separately and all sources combined. RESULTS: A total of 4499 patients were included. Patients with ≥1 mRNA COVID-19 vaccine dose were identified most frequently by self-report (n = 3570, 79 %), followed by IIS (n = 3272, 73 %) and EMR (n = 3057, 68 %). Agreement was highest between IIS and self-report for 4 doses with a kappa of 0.77 (95 % CI = 0.73-0.81). VE point estimates of 3 doses against COVID-19 hospitalization were substantially lower when using vaccination data from EMR only (VE = 31 %, 95 % CI = 16 %-43 %) than when using all sources combined (VE = 53 %, 95 % CI = 41 %-62%). CONCLUSION: Vaccination data from EMR only may substantially underestimate COVID-19 VE.

Early Serial Echocardiographic and Ultrasonographic Findings in Critically Ill Patients With COVID-19

Background Cardiac function of critically ill patients with COVID-19 generally has been reported from clinically obtained data. Echocardiographic deformation imaging can identify ventricular dysfunction missed by traditional echocardiographic assessment. Research Question What is the prevalence of ventricular dysfunction and what are its implications for the natural history of critical COVID-19? Study Design and Methods This is a multicenter prospective cohort of critically ill patients with COVID-19. We performed serial echocardiography and lower extremity vascular ultrasound on hospitalization days 1, 3, and 8. We defined left ventricular (LV) dysfunction as the absolute value of longitudinal strain of < 17% or LV ejection fraction (LVEF) of < 50%. Primary clinical outcome was inpatient survival. Results We enrolled 110 patients. Thirty-nine (35.5%) died before hospital discharge. LV dysfunction was present at admission in 38 patients (34.5%) and in 21 patients (36.2%) on day 8 (P = .59). Median baseline LVEF was 62% (interquartile range [IQR], 52%-69%), whereas median absolute value of baseline LV strain was 16% (IQR, 14%-19%). Survivors and nonsurvivors did not differ statistically significantly with respect to day 1 LV strain (17.9% vs 14.4%;P = .12) or day 1 LVEF (60.5% vs 65%;P = .06). Nonsurvivors showed worse day 1 right ventricle (RV) strain than survivors (16.3% vs 21.2%;P = .04). Interpretation Among patients with critical COVID-19, LV and RV dysfunction is common, frequently identified only through deformation imaging, and early (day 1) RV dysfunction may be associated with clinical outcome.

The Impact of the COVID-19 Pandemic on Sexual Behavior and HIV Prevention and Treatment Services Among U.S. Men Who Have Sex With Men in the Post-Lockdown Era.

Early in the COVID-19 pandemic, disruptions to sexual health services and changes to sexual behavior due to the first COVID-19 lockdowns were common among U.S. gay, bisexual, and other men who have sex with men (GBMSM). Less is known about the persistence of these changes after this initial lockdown period. These changes have long-term implications for HIV prevention for current and future pandemic periods. This study collected information on COVID-related impacts on sexual behavior and HIV-related health service disruptions from a cohort of U.S. GBMSM at three time points during the COVID-19 pandemic. We observed that COVID-related disruptions to sexual behavior continued from early lockdown periods through December 2020. Although early interruptions to pre-exposure prophylaxis (PrEP) access resolved in later 2020 and interruptions to antiretroviral therapy (ART) adherence were minimal, extended disruptions were observed in HIV testing, sexually transmitted infection (STI) testing, HIV care clinical visits, and HIV viral load testing. Although sexual behavior did not return to prepandemic levels in late 2020, the reduced access to HIV prevention, testing, and treatment services during this period could result in an overall increased HIV transmission rate, with long-term impacts to the trajectory of the U.S. HIV epidemic. Additional resources and programs are needed to address challenges created by the COVID-19 pandemic, as well as prepare for future potential pandemics and other disruptive events.

Resurgence of Omicron BA.2 in SARS-CoV-2 infection-naive Hong Kong.

Hong Kong experienced a surge of Omicron BA.2 infections in early 2022, resulting in one of the highest per-capita death rates of COVID-19. The outbreak occurred in a dense population with low immunity towards natural SARS-CoV-2 infection, high vaccine hesitancy in vulnerable populations, comprehensive disease surveillance and the capacity for stringent public health and social measures (PHSMs). By analyzing genome sequences and epidemiological data, we reconstructed the epidemic trajectory of BA.2 wave and found that the initial BA.2 community transmission emerged from cross-infection within hotel quarantine. The rapid implementation of PHSMs suppressed early epidemic growth but the effective reproduction number (Re) increased again during the Spring festival in early February and remained around 1 until early April. Independent estimates of point prevalence and incidence using phylodynamics also showed extensive superspreading at this time, which likely contributed to the rapid expansion of the epidemic. Discordant inferences based on genomic and epidemiological data underscore the need for research to improve near real-time epidemic growth estimates by combining multiple disparate data sources to better inform outbreak response policy.

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Effectiveness of Monovalent mRNA COVID-19 Vaccination in Preventing COVID-19-Associated Invasive Mechanical Ventilation and Death Among Immunocompetent Adults During the Omicron Variant Period - IVY Network, 19 U.S. States, February 1, 2022-January 31, 2023.

As of April 2023, the COVID-19 pandemic has resulted in 1.1 million deaths in the United States, with approximately 75% of deaths occurring among adults aged ≥65 years (1). Data on the durability of protection provided by monovalent mRNA COVID-19 vaccination against critical outcomes of COVID-19 are limited beyond the Omicron BA.1 lineage period (December 26, 2021-March 26, 2022). In this case-control analysis, the effectiveness of 2-4 monovalent mRNA COVID-19 vaccine doses was evaluated against COVID-19-associated invasive mechanical ventilation (IMV) and in-hospital death among immunocompetent adults aged ≥18 years during February 1, 2022-January 31, 2023. Vaccine effectiveness (VE) against IMV and in-hospital death was 62% among adults aged ≥18 years and 69% among those aged ≥65 years. When stratified by time since last dose, VE was 76% at 7-179 days, 54% at 180-364 days, and 56% at ≥365 days. Monovalent mRNA COVID-19 vaccination provided substantial, durable protection against IMV and in-hospital death among adults during the Omicron variant period. All adults should remain up to date with recommended COVID-19 vaccination to prevent critical COVID-19-associated outcomes.

Consistent Effects of Early Remdesivir on Symptoms and Disease Progression Across At-Risk Outpatient Subgroups: Treatment Effect Heterogeneity in PINETREE Study.

INTRODUCTION: In the PINETREE study, early remdesivir treatment reduced risk of coronavirus disease 2019 (COVID-19)-related hospitalizations or all-cause death versus placebo by 87% by day 28 in high-risk, non-hospitalized patients. Here we report results of assessment of heterogeneity of treatment effect (HTE) of early outpatient remdesivir, focusing on time from symptom onset and number of baseline risk factors (RFs). METHODS: PINETREE was a double-blind, placebo-controlled trial of non-hospitalized patients with COVID-19 who were randomized within 7 days of symptom onset and had ≥ 1 RF for disease progression (age ≥ 60 years, obesity [body mass index ≥ 30], or certain coexisting medical conditions). Patients received remdesivir intravenously (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. RESULTS: In this subgroup analysis, HTE of remdesivir by time from symptom onset at treatment initiation and number of baseline RFs was not detected. Treatment with remdesivir reduced COVID-19-related hospitalizations independent of stratification by time from symptom onset to randomization. Of patients enrolled ≤ 5 days from symptom onset, 1/201 (0.5%) receiving remdesivir and 9/194 (4.6%) receiving placebo were hospitalized (hazard ratio [HR] 0.10; 95% confidence interval [CI] 0.01-0.82). Of those enrolled at > 5 days from symptom onset, 1/78 (1.3%) receiving remdesivir and 6/89 (6.7%) receiving placebo were hospitalized (HR 0.19; 95% CI 0.02-1.61). Remdesivir was also effective in reducing COVID-19-related hospitalizations when stratified by number of baseline RFs for severe disease. Of patients with ≤ 2 RFs, 0/159 (0.0%) receiving remdesivir and 4/164 (2.4%) receiving placebo were hospitalized; of those with ≥ 3 RFs, 2/120 (1.7%) receiving remdesivir and 11/119 (9.2%) receiving placebo were hospitalized (HR 0.16; 95% CI 0.04-0.73). CONCLUSIONS: In the outpatient setting, benefit of remdesivir initiated within 7 days of symptoms appeared to be consistent across patients with RFs. Therefore, it may be reasonable to broadly treat patients with remdesivir regardless of comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov number NCT04501952.