RSV Vaccine Effectiveness Against Hospitalization Among US Adults 60 Years and Older.

This study evaluates the effectiveness of the respiratory syncytial virus vaccine against hospitalization for acute respiratory illness among US adults aged 60 years and older.

Influenza A virus within-host evolution and positive selection in a densely sampled household cohort over three seasons.

While influenza A virus (IAV) antigenic drift has been documented globally, in experimental animal infections, and in immunocompromised hosts, positive selection has generally not been detected in acute infections. This is likely due to challenges in distinguishing selected rare mutations from sequencing error, a reliance on cross-sectional sampling, and/or the lack of formal tests of selection for individual sites. Here, we sequenced IAV populations from 346 serial, daily nasal swabs from 143 individuals collected over three influenza seasons in a household cohort. Viruses were sequenced in duplicate, and intrahost single nucleotide variants (iSNV) were identified at a 0.5% frequency threshold. Within-host populations were subject to purifying selection with >75% mutations present at <2% frequency. Children (0-5 years) had marginally higher within-host evolutionary rates than adolescents (6-18 years) and adults (>18 years, 4.4×10-6 vs. 9.42×10-7 and 3.45×10-6, p <0.001). Forty-five iSNV had evidence of parallel evolution, but were not overrepresented in HA and NA. Several increased from minority to consensus level, with strong linkage among iSNV across segments. A Wright Fisher Approximate Bayesian Computational model identified positive selection at 23/256 loci (9%) in A(H3N2) specimens and 19/176 loci (11%) in A(H1N1)pdm09 specimens, and these were infrequently found in circulation. Overall, we found that within-host IAV populations were subject to purifying selection and genetic drift, with only subtle differences across seasons, subtypes, and age strata. Positive selection was rare and inconsistently detected.

Influenza virus shedding and symptoms: Dynamics and implications from a multiseason household transmission study.

Isolation of symptomatic infectious persons can reduce influenza transmission. However, virus shedding that occurs without symptoms will be unaffected by such measures. Identifying effective isolation strategies for influenza requires understanding the interplay between individual virus shedding and symptom presentation. From 2017 to 2020, we conducted a case-ascertained household transmission study using influenza real-time RT-qPCR testing of nasal swabs and daily symptom diary reporting for up to 7 days after enrolment (≤14 days after index onset). We assumed real-time RT-qPCR cycle threshold (Ct) values were indicators of quantitative virus shedding and used symptom diaries to create a score that tracked influenza-like illness (ILI) symptoms (fever, cough, or sore throat). We fit phenomenological nonlinear mixed-effects models stratified by age and vaccination status and estimated two quantities influencing isolation effectiveness: shedding before symptom onset and shedding that might occur once isolation ends. We considered different isolation end points (including 24 h after fever resolution or 5 days after symptom onset) and assumptions about the infectiousness of Ct shedding trajectories. Of the 116 household contacts with ≥2 positive tests for longitudinal analyses, 105 (91%) experienced ≥1 ILI symptom. On average, children <5 years experienced greater peak shedding, longer durations of shedding, and elevated ILI symptom scores compared with other age groups. Most individuals (63/105) shed <10% of their total shed virus before symptom onset, and shedding after isolation varied substantially across individuals, isolation end points, and infectiousness assumptions. Our results can inform strategies to reduce transmission from symptomatic individuals infected with influenza.

Estimating the generation time for influenza transmission using household data in the United States.

The generation time, representing the interval between infections in primary and secondary cases, is essential for understanding and predicting the transmission dynamics of seasonal influenza, including the real-time effective reproduction number (Rt). However, comprehensive generation time estimates for seasonal influenza, especially post the 2009 influenza pandemic, are lacking. We estimated the generation time utilizing data from a 7-site case-ascertained household study in the United States over two influenza seasons, 2021/2022 and 2022/2023. More than 200 individuals who tested positive for influenza and their household contacts were enrolled within 7 days of the first illness in the household. All participants were prospectively followed for 10 days completing daily symptom diaries and collecting nasal swabs, which were tested for influenza via RT-PCR. We analyzed these data by modifying a previously published Bayesian data augmentation approach that imputes infection times of cases to obtain both intrinsic (assuming no susceptible depletion) and realized (observed within household) generation times. We assessed the robustness of the generation time estimate by varying the incubation period, and generated estimates of the proportion of transmission before symptomatic onset, infectious period, and latent period. We estimated a mean intrinsic generation time of 3.2 (95% credible interval, CrI: 2.9-3.6) days, with a realized household generation time of 2.8 (95% CrI: 2.7-3.0) days. The generation time exhibited limited sensitivity to incubation period variation. Estimates of the proportion of transmission that occurred before symptom onset, the infectious period, and the latent period were sensitive to variation in incubation periods. Our study contributes to the ongoing efforts to refine estimates of the generation time for influenza. Our estimates, derived from recent data following the COVID-19 pandemic, are consistent with previous pre-pandemic estimates, and will be incorporated into real-time Rt estimation efforts.

Reduced Risk of SARS-CoV-2 Infection Among Household Contacts with Recent Vaccination and Past COVID-19 Infection: Results from Two Multi-Site Case-Ascertained Household Transmission Studies.

Households are a primary setting for transmission of SARS-CoV-2. We examined the role of prior SARS-CoV-2 immunity on the risk of infection in household close contacts. Households in the United States with an individual who tested positive for SARS-CoV-2 during September 2021-May 2023 were enrolled if the index case's illness began ≤6 days prior. Household members had daily self-collected nasal swabs tested by RT-PCR for SARS-CoV-2. The effects of prior SARS-CoV-2 immunity (vaccination, prior infection, or hybrid immunity) on SARS-CoV-2 infection risk among household contacts were assessed by robust, clustered multivariable Poisson regression. Of 1,532 contacts (905 households), 8% had immunity from prior infection alone, 51% from vaccination alone, 29% hybrid immunity, and 11% had no prior immunity. Sixty percent of contacts tested SARS-CoV-2-positive during follow-up. The adjusted risk of SARS-CoV-2 infection was lowest among contacts with vaccination and prior infection (aRR: 0.81, 95% CI: 0.70, 0.93, compared with contacts with no prior immunity) and was lowest when the last immunizing event occurred ≤6 months before COVID-19 affected the household (aRR: 0.69, 95% CI: 0.57, 0.83). In high-transmission settings like households, immunity from COVID-19 vaccination and prior infection was synergistic in protecting household contacts from SARS-CoV-2 infection.

Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity-IVY Network, 26 Hospitals, October 18, 2023-March 9, 2024.

BACKGROUND: Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial divergence from co-circulating XBB lineages. METHODS: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. RESULTS: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. CONCLUSIONS: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB.

Acceptance of a third COVID-19 vaccine dose, vaccine interchangeability, and clinical trial enrolment among parents of children 12-17 years in Lima, Perú.

Objectives: To characterize factors associated with parental willingness for their children participation in a COVID-19 vaccine trial, use of different COVID-19 vaccines and acceptance of a third vaccine dose. Methods: Parents of children aged 12-17 years in Lima, Perú were asked to complete an online questionnaire via social networks, from November 9, 2021, to April 23, 2022. We calculated crude and adjusted prevalence ratios with 95% confidence intervals to compare factors with the mentioned outcomes. Results: From 523 parents responding, 374 completed the survey. 90.4% would give their children a third vaccine dose, 36.6% would allow their children participation in a COVID-19 vaccine clinical trial, and 33.2% would accept different vaccine brands between doses. Parental belief that COVID-19 vaccine studies met quality standards was associated with acceptance of a third booster dose (adjusted PR 3.25; 95% CI1.57-6.74; p = 0.002), enrolment in a COVID-19 clinical trial (adjusted PR 4.49; 95% CI1.25-16.06; p = 0.02), and acceptance of different COVID-19 vaccine brands between doses (adjusted PR 10.02; 95% CI1.40-71.95; p = 0.02). Conclusion: Most parents would accept a third vaccine booster dose, approximately a third would participate in COVID-19 vaccine trials. Believing COVID-19 vaccines studies fulfilled quality standards was associated with the study outcomes. It is necessary to inform about the rigorous processes for the development of COVID-19 vaccines to generate confidence in parents to accept these vaccine-related outcomes.

Asymptomatic and mildly symptomatic influenza virus infections by season -- Case-ascertained household transmission studies, United States, 2017-2023.

Asymptomatic influenza virus infection occurs but may vary by factors such as age, influenza vaccination status, or influenza season. We examined the frequency of influenza virus infection and associated symptoms using data from two case-ascertained household transmission studies (conducted from 2017-2023) with prospective, systematic collection of respiratory specimens and symptoms. From the 426 influenza virus infected household contacts that met our inclusion criteria, 8% were asymptomatic, 6% had non-respiratory symptoms, 23% had acute respiratory symptoms, and 62% had influenza-like illness symptoms. Understanding the prevalence of asymptomatic and mildly symptomatic influenza cases is important for implementing effective influenza prevention strategies and enhancing the effectiveness of symptom-based surveillance systems.

Prevalence, Clinical Severity, and Serotype Distribution of Pneumococcal Pneumonia Among Adults Hospitalized With Community-Acquired Pneumonia in Tennessee and Georgia, 2018-2022.

INTRODUCTION: Understanding the pneumococcal serotypes causing community-acquired pneumonia (CAP) is essential for evaluating the impact of pneumococcal vaccines. METHODS: We conducted a prospective surveillance study of adults aged ≥18 years hospitalized with CAP at 3 hospitals in Tennessee and Georgia between 1 September 2018 and 31 October 2022. We assessed for pneumococcal etiology with cultures, the BinaxNOW urinary antigen detection test, and serotype-specific urinary antigen detection assays that detect 30 pneumococcal serotypes contained in the investigational pneumococcal conjugate vaccine V116, as well as licensed vaccines PCV15 and PCV20 (except serotype 15B). The distribution of pneumococcal serotypes was calculated based on serotype-specific urinary antigen detection results. RESULTS: Among 2917 hospitalized adults enrolled with CAP, 352 (12.1%) patients had Streptococcus pneumoniae detected, including 51 (1.7%) patients with invasive pneumococcal pneumonia. The 8 most commonly detected serotypes were: 3, 22F, 19A, 35B, 9N, 19F, 23A, and 11A. Among 2917 adults with CAP, 272 (9.3%) had a serotype detected that is contained in V116, compared to 196 (6.7%) patients with a serotype contained in PCV20 (P < .001), and 168 (5.8%) patients with a serotype contained in PCV15 (P < .001). A serotype contained in V116 but not PCV15 or PCV20 was detected in 120 (4.1%) patients, representing 38.0% of serotype detections. CONCLUSIONS: Approximately 12% of adults hospitalized with CAP had S. pneumoniae detected, and approximately one-third of the detected pneumococcal serotypes were not contained in PCV15 or PCV20. Development of new pneumococcal vaccines with expanded serotype coverage has the potential to prevent a substantial burden of disease.

Antibody Response to Symptomatic Infection With SARS-CoV-2 Omicron Variant Viruses, December 2021-June 2022.

We describe humoral immune responses in 105 ambulatory patients with laboratory-confirmed SARS-CoV-2 Omicron variant infection. In dried blood spot (DBS) collected within 5 days of illness onset and during convalescence, we measured binding antibody (bAb) against ancestral spike protein receptor binding domain (RBD) and nucleocapsid (N) protein using a commercial multiplex bead assay. Geometric mean bAb concentrations against RBD increased by a factor of 2.5 from 1258 to 3189 units/mL and by a factor of 47 against N protein from 5.5 to 259 units/mL between acute illness and convalescence; lower concentrations were associated with greater geometric mean ratios. Paired DBS specimens may be used to evaluate humoral response to SARS-CoV-2 infection.

Safety, tolerability, and immunogenicity of an adult pneumococcal conjugate vaccine, V116 (STRIDE-3): a randomised, double-blind, active comparator controlled, international phase 3 trial.

BACKGROUND: The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults. METHODS: This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732). FINDINGS: Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events. INTERPRETATION: V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20. FUNDING: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

A Phase 3 Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine-Experienced Adults 50 Years of Age or Older (Stride-6).

BACKGROUND: Pneumococcal diseases (PD) cause considerable morbidity and mortality in adults. V116 is an investigational 21-valent pneumococcal conjugate vaccine (PCV) specifically designed to protect adults from pneumococcal serotypes responsible for the majority of residual PD. This phase 3 study evaluated safety, tolerability, and immunogenicity of V116 in pneumococcal vaccine-experienced adults ≥50 years. METHODS: A total of 717 adults were enrolled to receive a single dose of pneumococcal vaccine as follows: Cohort 1 (n=350) previously received PPSV23 and were randomized 2:1 to receive V116 or PCV15, respectively; Cohort 2 (n=261) previously received PCV13 and were randomized 2:1 to receive V116 or PPSV23, respectively; Cohort 3 (n=106) previously received PPSV23+PCV13, PCV13+PPSV23, PCV15+PPSV23, or PCV15 and all received open-label V116. Immunogenicity was evaluated 30 days postvaccination using opsonophagocytic activity (OPA) geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) for all V116 serotypes. Safety was evaluated as the proportion of participants with adverse events (AEs). RESULTS: V116 was immunogenic across all 3 cohorts as assessed by serotype-specific OPA GMTs and IgG GMCs postvaccination for all 21 serotypes. V116 elicited comparable immune responses to serotypes shared with PCV15 (Cohort 1) or PPSV23 (Cohort 2), and higher immune responses to serotypes unique to V116. The proportions of participants with solicited AEs were generally comparable across cohorts. CONCLUSIONS: V116 is well tolerated with a safety profile comparable to currently licensed pneumococcal vaccines and generates IgG and functional immune responses to all V116 serotypes, regardless of prior pneumococcal vaccine received.

Anti-SARS-CoV-2 Antibody Levels Associated With COVID-19 Protection in Outpatients Tested for SARS-CoV-2, US Flu Vaccine Effectiveness Network, October 2021-June 2022.

BACKGROUND: We assessed associations between binding antibody (bAb) concentration <5 days from symptom onset and testing positive for COVID-19 among patients in a test-negative study. METHODS: From October 2021 to June 2022, study sites in 7 states enrolled patients aged ≥6 months presenting with acute respiratory illness. Respiratory specimens were tested for SARS-CoV-2. In blood specimens, we measured concentrations of anti-SARS-CoV-2 antibodies against the spike protein receptor binding domain (RBD) and nucleocapsid antigens from the ancestral strain in standardized bAb units (BAU). Percentage change in odds of COVID-19 by increasing anti-RBD bAb was estimated via logistic regression as (1 - adjusted odds ratio of COVID-19) × 100, adjusting for COVID-19 mRNA vaccine doses, age, site, and high-risk exposure. RESULTS: Out of 2018 symptomatic patients, 662 (33%) tested positive for acute SARS-CoV-2 infection. Geometric mean RBD bAb levels were lower among COVID-19 cases than SARS-CoV-2 test-negative controls during the Delta-predominant period (112 vs 498 BAU/mL) and Omicron-predominant period (823 vs 1189 BAU/mL). Acute-phase ancestral spike RBD bAb levels associated with 50% lower odds of COVID-19 were 1968 BAU/mL against Delta and 3375 BAU/mL against Omicron; thresholds may differ in other laboratories. CONCLUSIONS: During acute illness, antibody concentrations against ancestral spike RBD were associated with protection against COVID-19.

Association of Symptoms and Viral Culture Positivity for SARS-CoV-2-Tennessee, April-July 2020.

BACKGROUND: Understanding how symptoms are associated with SARS-CoV-2 culture positivity is important for isolation and transmission control guidelines. METHODS: Individuals acutely infected with SARS-CoV-2 in Tennessee and their household contacts were recruited into a prospective study. All participants self-collected nasal swabs daily for 14 days and completed symptom diaries from the day of illness onset through day 14 postenrollment. Nasal specimens were tested for SARS-CoV-2 using RT-qPCR. Positive specimens with cycle threshold values < 40 were sent to the Centers for Disease Control and Prevention (CDC) for viral culture. First, we modeled the association between symptoms and the risk of culture positivity using an age-adjusted generalized additive model (GAM) accounting for repeated measurements within participants and a symptom-day spline. Next, we investigated how timing of symptom resolution was associated with the timing of culture resolution. RESULTS: In a GAM restricted to follow-up days after symptoms began, the odds of a specimen being culture positive was significantly increased on days when wheezing, loss of taste or smell, runny nose, nasal congestion, sore throat, fever, or any symptom were reported. For all symptoms except sore throat, it was more common for participants to have culture resolution before symptom resolution than for culture to resolve after or on the same day as symptom resolution. CONCLUSIONS: Overall, symptomatic individuals were more likely to be SARS-CoV-2 viral culture positive. For most symptoms, culture positivity was more likely to end before symptoms resolved. However, a proportion of individuals remained culture positive after symptom resolved, across all symptoms.

Incidence of Influenza-associated Neurologic and Psychiatric Complications Requiring Hospitalization in Children Ages 5-17 Years.

BACKGROUND: The spectrum and incidence of influenza-associated neuropsychiatric complications are not well-characterized. The objective of this study was to define the incidence of specific neurologic and psychiatric complications associated with influenza in children and adolescents. METHODS: We assembled a retrospective cohort of children 5-17 years of age with an outpatient or emergency department International Classification of Diseases, 10th revision influenza diagnosis and enrolled in Tennessee Medicaid from 2016 to 2020. Serious neurologic or psychiatric complications requiring hospitalization were identified using a validated algorithm. Incidence rates of complications were expressed per 100,000 person-weeks of influenza and 95% confidence intervals (CIs) were reported. RESULTS: A total of 156,661 influenza encounters (median age of 9.3 years) were included. The overall incidence of neurologic complications was 30.5 (95% CI: 24.0-38.6) per 100,000 person-weeks of influenza and 1880.9 (95% CI: 971.9-3285.5) among children with an underlying neurologic comorbidity. The distribution of antiviral treatment was similar among those with and without neurologic or psychiatric complications. The overall incidence of psychiatric complications was 20.2 (95% CI: 15.1-27.0) per 100,000 person-weeks of influenza and 111.8 (95% CI: 77.9-155.5) among children with an underlying psychiatric comorbidity. Seizures (17.5, 95% CI: 12.8-23.9) were the most common neurologic complications whereas encephalitis (0.5, 95% CI: 0.02-2.5) was rare. Mood disorders (17.5, 95% CI: 12.8-23.9) were the most frequent psychiatric complications and self-harm events (0.9, 95% CI: 0.3-3.3) were the least common. DISCUSSION: Our findings reveal that the incidence of neuropsychiatric complications of influenza is overall low; however, the incidence among children with underlying neurologic or psychiatric condition is significantly higher than among children without these conditions.

Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity - IVY Network, 26 Hospitals, October 18, 2023-March 9, 2024.

Background: Assessing COVID-19 vaccine effectiveness (VE) and severity of SARS-CoV-2 variants can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial genomic divergence from co-circulating XBB lineages. Methods: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated the effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. Results: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. Conclusions: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB lineage hospitalizations.

The impact of different strategies for modeling associations between medications at low doses and health outcomes: a simulation study and practical application to postpartum opioid use.

Pharmacoepidemiological studies commonly examine the association between drug dose and adverse health outcomes. In situations where no safe dose exists, the choice of modeling strategy can lead to identification of an apparent safe low dose range in the presence of a non-linear relationship or due to the modeling strategy forcing a linear relationship through a dose of 0. We conducted a simulation study to assess the performance of several regression approaches to model the drug dose-response curve at low doses in a setting where no safe range exists, including the use of a (1) linear dose term, (2) categorical dose term, and (3) natural cubic spline terms. Additionally, we introduce and apply an expansion of prior work related to modeling dose-response curves at low and infrequently used doses in the setting of no safe dose ("spike-at-zero" and "slab-and-spline"). Furthermore, we demonstrate and empirically assess the use of these regression strategies in a practical scenario examining the association between the dose of the initial postpartum opioid prescribed after vaginal delivery and the subsequent total dose of opioids prescribed in the entire postpartum period among a cohort of opioid-naïve women with a vaginal delivery enrolled in a State Medicaid program (2007-2014).

Prognostic clinical decision support for pneumonia in the emergency department: A randomized trial.

BACKGROUND: Hospitalization rates for childhood pneumonia vary widely. Risk-based clinical decision support (CDS) interventions may reduce unwarranted variation. METHODS: We conducted a pragmatic randomized trial in two US pediatric emergency departments (EDs) comparing electronic health record (EHR)-integrated prognostic CDS versus usual care for promoting appropriate ED disposition in children (<18 years) with pneumonia. Encounters were randomized 1:1 to usual care versus custom CDS featuring a validated pneumonia severity score predicting risk for severe in-hospital outcomes. Clinicians retained full decision-making authority. The primary outcome was inappropriate ED disposition, defined as early transition to lower- or higher-level care. Safety and implementation outcomes were also evaluated. RESULTS: The study enrolled 536 encounters (269 usual care and 267 CDS). Baseline characteristics were similar across arms. Inappropriate disposition occurred in 3% of usual care encounters and 2% of CDS encounters (adjusted odds ratio: 0.99, 95% confidence interval: [0.32, 2.95]). Length of stay was also similar and adverse safety outcomes were uncommon in both arms. The tool's custom user interface and content were viewed as strengths by surveyed clinicians (>70% satisfied). Implementation barriers include intrinsic (e.g., reaching the right person at the right time) and extrinsic factors (i.e., global pandemic). CONCLUSIONS: EHR-based prognostic CDS did not improve ED disposition decisions for children with pneumonia. Although the intervention's content was favorably received, low subject accrual and workflow integration problems likely limited effectiveness. Clinical Trials Registration: NCT06033079.

Estimating the Undetected Burden of Respiratory Syncytial Virus Hospitalizations in Adults Through Capture-Recapture Methods.

INTRODUCTION: Traditional surveillance systems may underestimate the burden caused by respiratory syncytial virus (RSV). Capture-recapture methods provide alternatives for estimating the number of RSV-related hospitalizations in a population. METHODS: Capture-recapture methods were used to estimate the number of RSV-related hospitalizations in adults in Middle Tennessee from two independent hospitalization surveillance systems during consecutive respiratory seasons from 2016-2017 to 2019-2020. Data from the Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) and the Emerging Infections Program (EIP) were used. Annual RSV hospitalization rates were calculated using the capture-recapture estimates weighted by hospitals' market share divided by the corresponding census population. RESULTS: Using capture-recapture methods, the estimated overall adult hospitalization rates varied from 8.3 (95% CI: 5.9-15.4) RSV-related hospitalizations per 10,000 persons during the 2016-2017 season to 28.4 (95% CI: 18.2-59.0) hospitalizations per 10,000 persons in the 2019-2020 season. The proportion of hospitalizations that HAIVEN determined ranged from 8.7% to 36.7% of the total capture-recapture estimated hospitalization, whereas EIP detected 23.5% to 52.7% of the total capture-recapture estimated hospitalizations. CONCLUSION: Capture-recapture estimates showed that individual traditional surveillance systems underestimated the hospitalization burden in adults. Using capture-recapture allows for a more comprehensive estimate of RSV hospitalizations.

Severity of Respiratory Syncytial Virus vs COVID-19 and Influenza Among Hospitalized US Adults.

Importance: On June 21, 2023, the Centers for Disease Control and Prevention recommended the first respiratory syncytial virus (RSV) vaccines for adults aged 60 years and older using shared clinical decision-making. Understanding the severity of RSV disease in adults can help guide this clinical decision-making. Objective: To describe disease severity among adults hospitalized with RSV and compare it with the severity of COVID-19 and influenza disease by vaccination status. Design, Setting, and Participants: In this cohort study, adults aged 18 years and older admitted to the hospital with acute respiratory illness and laboratory-confirmed RSV, SARS-CoV-2, or influenza infection were prospectively enrolled from 25 hospitals in 20 US states from February 1, 2022, to May 31, 2023. Clinical data during each patient's hospitalization were collected using standardized forms. Data were analyzed from August to October 2023. Exposures: RSV, SARS-CoV-2, or influenza infection. Main Outcomes and Measures: Using multivariable logistic regression, severity of RSV disease was compared with COVID-19 and influenza severity, by COVID-19 and influenza vaccination status, for a range of clinical outcomes, including the composite of invasive mechanical ventilation (IMV) and in-hospital death. Results: Of 7998 adults (median [IQR] age, 67 [54-78] years; 4047 [50.6%] female) included, 484 (6.1%) were hospitalized with RSV, 6422 (80.3%) were hospitalized with COVID-19, and 1092 (13.7%) were hospitalized with influenza. Among patients with RSV, 58 (12.0%) experienced IMV or death, compared with 201 of 1422 unvaccinated patients with COVID-19 (14.1%) and 458 of 5000 vaccinated patients with COVID-19 (9.2%), as well as 72 of 699 unvaccinated patients with influenza (10.3%) and 20 of 393 vaccinated patients with influenza (5.1%). In adjusted analyses, the odds of IMV or in-hospital death were not significantly different among patients hospitalized with RSV and unvaccinated patients hospitalized with COVID-19 (adjusted odds ratio [aOR], 0.82; 95% CI, 0.59-1.13; P = .22) or influenza (aOR, 1.20; 95% CI, 0.82-1.76; P = .35); however, the odds of IMV or death were significantly higher among patients hospitalized with RSV compared with vaccinated patients hospitalized with COVID-19 (aOR, 1.38; 95% CI, 1.02-1.86; P = .03) or influenza disease (aOR, 2.81; 95% CI, 1.62-4.86; P < .001). Conclusions and Relevance: Among adults hospitalized in this US cohort during the 16 months before the first RSV vaccine recommendations, RSV disease was less common but similar in severity compared with COVID-19 or influenza disease among unvaccinated patients and more severe than COVID-19 or influenza disease among vaccinated patients for the most serious outcomes of IMV or death.