Open Forum Infectious Diseases

ObjectiveReal-world data on the effectiveness of boosters against COVID-19, especially as new variants continue to emerge, is limited. It is our objective to assess demographic, clinical, and outcome variables of patients requiring hospitalization for severe SARS-CoV-2 infection comparing fully vaccinated and boosted (FV&B) and unvaccinated (UV) patients. MethodsThis multicenter observational cohort analysis compared demographic, clinical, and outcome variables in FV&B and UV adults hospitalized for COVID-19. A sub-analysis of FV&B patients requiring intensive care (ICU) care versus non-ICU care was performed to describe and analyze common symptom presentations, initial vital signs, initial laboratory workup, and pertinent medication use in these two groups. ResultsBetween August 12th, 2021 and December 6th, 2021, 4,571 patient encounters had a primary diagnosis of COVID-19 and required inpatient treatment at an acute-care hospital system in Southeastern Michigan. Of the 4,571 encounters requiring hospitalization, 65(1.4%) were FV&B and 2,935(64%) were UV. FV&B individuals were older (74 [67, 81] vs 58 [45, 70]; p <0.001) with a higher proportion of immunocompromised individuals (32.3% vs 10.4%; p<0.001). Despite a significantly higher baseline risk of in-hospital mortality in the FV&B group compared to the UV (Elixhauser 16 vs 8 (p <0.001)), there was a trend toward lower in-hospital mortality (7.7% vs 12.1%; p=0.38) among FV&B patients. Other severe outcomes followed this same trend, with 7.7% of FV&B vs 11.1% UV patients needing mechanical ventilation and 4.6% vs 10.6% of patients needing vasopressors in each group, respectively (p=0.5 and 0.17). ConclusionsFully vaccinated and boosted individuals requiring hospital-level care for breakthrough COVID-19 tended to have less severe outcomes despite appearing to be higher risk at baseline when compared to unvaccinated individuals during the same time period. Specifically, there was a trend that FV&B group had lower rates of mechanical ventilation, use of vasopressors, and in-hospital mortality. As COVID-19 continues to spread, larger expansive trials are needed to further identify risk factors for severe outcomes among the FV&B population.

BackgroundEvidence supports the key role research mentors play in bolstering the success of early stage investigators (ESI). However, there are limited data about the impact of supplemental, cross-disciplinary career mentorship and professional development opportunities for ESIs seldom included during academic training. We assessed the perceived value of this approach among post-doctoral fellows and early career faculty who participated in a multi-component career mentoring program organized by the University of California, San Francisco Center for AIDS Research (UCSF CFAR). MethodsWe surveyed past program participants (2005-2020), assessing demographics, current career status, perceived impact of the program, and feedback on program elements. We performed thematic analysis on open-ended responses to explore program benefits. ResultsOf 146 program participants contacted, 102 responded (70% response rate). Over two thirds (65%) were female, and 38% self-identified as underrepresented minority (URM) investigators. A majority of respondents now dedicate >70% of their time to research. All would recommend the program to ESI colleagues, and over 80% reported that their CFAR mentors influenced their career trajectories in several ways, including help with grant writing, linkage to researchers sparking new collaborations, and support through personal challenges or navigating conflict with primary research mentors. While 90% of URM ESIs valued advice from CFAR mentors, only a third reported receiving specific support around challenges faced as minoritized investigators. ConclusionsA career mentoring program designed to complement the support offered by research mentors positively influenced the career trajectory of ESIs. Focused efforts are needed to support URM investigators who face ongoing structural barriers to success in academic settings.

We describe early outcomes in 11 COVID-19 patients treated with the IL-6 receptor inhibitor tocilizumab. While C-reactive protein decreased, neither clinical improvement nor reduced temperature or oxygen requirements was observed in most patients. Our findings contrast with prior reports and raise questions about tocilizumab use in severe COVID-19.

BackgroundVaccine products for adults have increased interest in understanding Canadas respiratory syncytial virus (RSV) burden in older adults and adults considered at high risk of severe infection. ObjectiveTo characterize the burden of RSV disease in Canada by joint analysis of the published literature and hospitalization data from a healthcare administrative database. MethodsElectronic databases of published literature were searched to identify studies and systematic reviews reporting data on outpatient visits, hospitalizations, intensive care unit (ICU) admissions and deaths associated with RSV infection in adults. For the hospitalization data analysis, hospital discharge records were extracted from the Canadian Institute of Health Information (CIHI) Discharge Abstract Database (DAD) for all patients admitted to an acute care facility for RSV infection defined by ICD-10 codes from 2010-2020 and 2021-2023. ResultsOverall, 26 studies, including 7 systematic reviews, were identified and summarized in the rapid review. Evidence suggests that medically attended RSV respiratory tract infections (RTI) are frequent causing 4.7 to 7.8% of symptomatic RTI in adults 60 years of age and older. Incidence of RSV RTI increases with age and presence of underlying medical conditions, such as cardiorespiratory disease, diabetes, and immunocompromising conditions. This trend was consistently observed across all RSV clinical outcomes of interest (i.e., hospitalization, ICU admission and death). Patients who reside in long-term care or other chronic care facilities have higher likelihood of severe clinical outcomes (i.e., ICU admission, receiving mechanical ventilation and/or death) compared to patients with other living situations upon hospital admission. Approximately 10% of older adults hospitalized with RSV infection require ICU admission. Although data are limited, evidence suggests that case fatality ratio (CFR) among those admitted to hospital varies between 5 and 10%. Some evidence suggests that RSV burden may be close to influenza burden in older adults. In general, the results from the Canadian hospitalization data support the rapid review findings Rates of hospitalization, ICU admission and death associated with RSV all increased with age, with 16% of hospitalizations resulting in ICU admission and with an in-hospital CFR of 9%. ConclusionIn adults, risk of severe RSV outcomes in general increases with increasing age and presence of comorbidities.

Background and objectivesAlthough clinical trials have shown that nirsevimab is safe, post-licensure safety data from routine settings are lacking. This study describes parent-reported health events occurring within seven days of nirsevimab administration in Canada. MethodsPost-licensure, active, safety surveillance of nirsevimab during the 2024-25 viral season in Canada, based on parent-completed questionnaires seven days after immunization. ResultsParents or caregivers of 1,559 children completed the survey. A third (454/1,559) of children had received nirsevimab co-administered with routine vaccines. Local injection-site reactions were reported in 140 children (9.0%), 79/454, 17.4%, [95%CI: 14.2-21.3] when nirsevimab was co-administered and 61/1,105, 5.5% [95%CI: 4.3-7.1] when nirsevimab was given alone. Injection-site reactions extending beyond the closest joint were infrequent (6/1,559, 0.4%). Health events that prevented daily activities or required a healthcare consultation were reported in 38/1,105 (3.4%) cases with nirsevimab administered alone and 19/454 (4.2%) with nirsevimab co-administered. The most reported symptoms were rhinorrhea: 1.8%, cough: 1.7%, feeding/eating changes: 1.6%, fever: 1.6% and diarrhea or change in bowel habits: 1.5%. Rash occurred in 10 children (0.6%). No cases of anaphylaxis were reported. ConclusionsThis study showed nirsevimab was well tolerated, with low incidence of health events within seven days of immunization. Results after co-administration support incorporation of nirsevimab into the routine vaccination schedule. Documenting parent-reported outcomes in post-licensure settings expands the safety data obtained from clinical trials and offers transparent, timely additional reassuring data to enhance parental confidence in RSV antibody interventions.

BackgroundRespiratory syncytial virus (RSV) is an important cause of acute respiratory illness in older adults, yet data from sub-Saharan Africa remain scarce. Understanding prevalence, coinfections, and risk factors in this age group is critical for guiding surveillance and prevention. MethodsWe conducted a retrospective cross-sectional study using Ugandas national influenza-like illness (ILI) and severe acute respiratory infection (SARI) sentinel surveillance data from December 2010 to January 2025. Adults aged [&ge;]65 years with Real time-PCR (RT-PCR) results for RSV, influenza A/B, and SARS-CoV-2 were included. Descriptive analyses summarized period prevalence, clinical characteristics, and temporal trends. Poisson regression with robust variance estimated adjusted prevalence ratios (aPRs) for factors associated with RSV infection and hospitalization. ResultsAmong 545 illness episodes (mean age 73.2 years; 54.1% female), the period prevalence of RSV across 2010-2025 was 4.8% (95% CI: 3.3-6.9), comparable to influenza A (4.2%) and lower than SARS-CoV-2 (6.4%). Most RSV cases were mono-infections (92.3%), with rare RSV-influenza coinfections (0.4%) and no RSV-SARS-CoV-2 coinfections. Asthma (aPR 6.08, 95% CI: 1.18-31.26, p=0.031) and pneumonia (aPR 2.83, 95% CI: 1.06-7.56, p=0.038) were independent predictors of RSV infection. Hospitalization was strongly associated with asthma (aPR 21.69, 95% CI: 7.50-62.71, p<0.001), pneumonia (aPR 3.80, 95% CI: 1.51-9.56, p=0.005), and heart disease (aPR 3.50, 95% CI: 1.03-11.91, p=0.045). RSV activity showed seasonal peaks in March and June, with a marked decline during 2020-2021 (COVID-19 restrictions) and resurgence thereafter. ConclusionsRSV is a consistent contributor to respiratory illness among older Ugandan adults, with period prevalence estimates similar to influenza A and clinically important associations with asthma and pneumonia. Seasonal peaks during the dry season and post-pandemic resurgence emphasize the need for RSV integration into surveillance and the timely introduction of preventive interventions, including vaccination, in low- and middle-income settings.

ImportanceAspergillosis is an under-recognized fungal infection associated with rising hospitalizations, concerns about antifungal resistance, and substantial morbidity and mortality in the U.S. Yet, national data on aspergillosis remain fragmented due to absence of centralized surveillance. ObjectiveTo examine demographic and geographic variation and temporal trends in aspergillosis prevalence in the U.S. from 2013 to 2023; to assess how the COVID-19 pandemic influenced prevalence across population subgroups. DesignRetrospective cohort study using a large, national electronic health record (EHR) database. Setting142 healthcare systems in the U.S. using Oracle Health EHR systems, encompassing disparate care settings. ParticipantsAdults aged 18 years and older who received care between January 1, 2013, and December 31, 2023. The cohort included over 76 million patients, and over 127 million person-years, with 20,764 aspergillosis diagnoses. ExposuresCalendar year, patient characteristics (age, sex, race, ethnicity, residence type), and state of residence. COVID-19 was treated as a time-varying exposure. Main Outcomes and MeasuresAnnual and overall prevalence of aspergillosis per 100,000 person-years; adjusted prevalence ratios (aPRs) by demographic group and state, estimated using quasi-Poisson and Bayesian spatiotemporal regression. COVID-19-related shifts in prevalence were assessed using estimated marginal means. ResultsBetween 2013 and 2023, aspergillosis prevalence increased 5% annually, peaking in 2022. Rhode Island had the highest aPR across all years; Utah the lowest. Prevalence was higher in males (aPR: 1.37), older adults (aPR for [&ge;]65 vs. 18 to 34: 4.95), and urban residents (rural aPR: 0.86). Post-COVID-19, prevalence increased disproportionately among Hispanic or Latino patients and several racial minority groups. Suggestive trends of increasing prevalence were also observed among rural residents. Conclusions and RelevanceThis study provides the most comprehensive national assessment to date of aspergillosis patterns in the U.S., revealing evidence of rising prevalence and emerging disparities shaped by the COVID-19 pandemic. Clinicians should consider regional and demographic risk patterns to support earlier diagnosis, guide antifungal treatment, and improve outcomes--especially among older adults and populations disproportionately affected by COVID-19. Clinicians practicing in rural or underserved areas should be particularly mindful of shifting risk profiles and advocate for improved diagnostic resources to reduce delays in care. Key Points QuestionHow has aspergillosis prevalence changed in the U.S. over time, and how did the COVID-19 pandemic influence prevalence among demographic and geographic subgroups? FindingsIn a nationally representative EHR cohort of over 76 million adults, aspergillosis prevalence increased by 5% annually from 2013 to 2023. After the emergence of COVID-19, prevalence increased disproportionately among Hispanic or Latino patients and racial minority groups. MeaningFindings suggest increasing aspergillosis prevalence in the U.S., with indications of widening disparities. While subject to data limitations, these trends underscore the importance of considering regional and demographic factors in clinical decision-making, particularly for populations disproportionately affected by COVID-19.

BackgroundTularemia is a bacterial disease caused by the intracellular bacterium Francisella tularensis (F. tularensis or Ft). It has been weaponized historically by multiple state actors due to its low infectious aerosol dose, high morbidity and high mortality rate of the pneumonic form. The US Army developed the attenuated Live Vaccine Strain (LVS) from stocks provided by the former Soviet Union in the 1950s. The vaccine has proven to be safe and immunogenic over the ensuing decades in numerous clinical trials and animal as well as human challenge studies. Despite the threat, there are no FDA-approved vaccines nor clinical stage candidates against tularemia. LVS remains unlicensed due to instability in culture and the potential for reversion to the wild-type pathogen. We report here two sequential LVS trials in at-risk laboratory personnel working on tularemia in bio-containment. MethodsVolunteers received a single dose of the Live Vaccine Strain (LVS) live, attenuated tularemia vaccine by scarification under 2 FDA-regulated non-randomized, single-arm protocols (IND 157). Positive immunization was based on local scarification site take reaction, and either a >1:20 tularemia antigen microagglutination (MA) titer (protocol FY03-24; 2004-8) or greater than 4-fold rise in MA titer (protocol FY07-15; 2009-2017). Those still negative by week 4 were offered a second dose. ResultsThe LVS vaccine was safe, well tolerated and highly immunogenic. Between the two studies, all recipients (100%) had positive take reactions, with 95.5% of those in study FY03-24 having a positive response following initial vaccination. All but 3 subjects (98%) in protocol FY03-24 had positive MA titer results defined as >1:20, most within 28-35 days. In protocol FY07-15, 95% of subjects had a 4-fold or greater rise in MA titer, the primary immunogenicity endpoint for that study. ConclusionsLVS vaccine administered to laboratory workers at risk for tularemia exposure over a 12 year period was safe and highly immunogenic. Findings were in line with more than 4 decades of prior similar results. Response rates remained robust despite the vaccine lots employed having been manufactured 2-3 decades prior to the present studies. In the absence of a commercial development effort, or another tularemia vaccine in clinical development, a vaccine protocol under investigational new drug (IND) application could be considered based on the large body of favorable data for this vaccine. The results as well as historical comparator data presented here should serve as a benchmark for future studies.

BackgroundHealthcare workers are perceived to be a high-risk group for acquiring SAR-CoV-2 infection, and more so in countries where COVID-19 vaccination uptake is low. Serosurveillance may best determine the true extent of SARS-CoV-2 infection since most infected HCWs may be asymptomatic or present with only mild symptoms. Over time, determining the true extent of SARS-CoV-2 infection could inform hospital management and staff whether the preventive measures instituted are effective and valuable in developing targeted solutions. MethodsThis was a census survey study conducted at the Aga Khan University Hospital, Nairobi, between November 2020 and February 2021 before the implementation of the COVID-19 vaccination. The SARS-CoV-2 nucleocapsid IgG test was performed using a chemiluminescent assay. ResultsOne thousand six hundred thirty-one (1631) staff enrolled, totalling 60% of the workforce. The overall crude seroprevalence was 18.4% and the adjusted value (for assay sensitivity of 86%) was 21.4% (95% CI; 19.2-23.7). The HCW groups with higher prevalence included pharmacy (25.6%), outreach (24%), hospital-based nursing (22.2%) and catering staff (22.6%). Independent predictors of a positive IgG result included prior COVID-19 like symptoms, odds ratio (OR) 1.9 [95% confidence interval (CI) 1.3-2.9, p=0.002], and a prior positive SARS-CoV-2 PCR result OR 11.0 (CI: 7.2-18.0, p<0.001). Age, sex, comorbidities or working in a COVID-19 designated area were not associated with seropositivity. The odds of testing positive for IgG after a positive PCR test were lowest if the antibody test was performed more than 2 months later; OR 0.7 (CI: 0.48-0.95, p= 0.025). ConclusionsThe prevalence of anti-SARS-CoV-2 nucleocapsid IgG among HCWs was lower than in the general population. Staff working in clinical areas were not at increased risk when compared to staff working in non-clinical areas.

Early reports showed high mortality from Covid-19; by contrast, the current outbreaks in the southern and western United States are associated with fewer deaths, raising hope that treatments have improved. However, in Texas for instance, 63% of diagnosed cases are currently under 50, compared to only 52% nationally in March-April. Current demographics in Arizona and Florida are similar. Therefore, whether decreasing Covid-19 mortality rates are a reflection of changing demographics or represent improvements in clinical care is unknown. We assessed outcomes over time in a single health system, accounting for changes in demographics and clinical factors. Methods We analyzed biweekly mortality rates for admissions between March 1 and June 20, 2020 in a single health system in New York City. Outcomes were obtained as of July 14, 2020. We included all hospitalizations with laboratory-confirmed Covid-19 disease. Patients with multiple hospitalizations (N=157, 3.3%) were included repeatedly if they continued to have laboratory-confirmed disease. Mortality was defined as in-hospital death or discharge to hospice care. Based on prior literature, we constructed a multivariable logistic regression model to generate expected risk of death, adjusting for age; sex; self-reported race and ethnicity; body mass index; smoking history; presence of hypertension, heart failure, hyperlipidemia, coronary artery disease, diabetes, cancer, chronic kidney disease, or pulmonary disease individually as dummy variables; and admission oxygen saturation, D-dimer, C reactive protein, ferritin, and cycle threshold for RNA detection. All data were obtained from the electronic health record. We then calculated the sum of observed and expected deaths in each two-week period and multiplied each period's observed/expected (O/E) risk by the overall average crude mortality to generate biweekly adjusted rates. We calculated Poisson control limits and indicated points outside the control limits as significantly different, following statistical process control standards. The NYU institutional review board approved the study and granted a waiver of consent. Results We included 4,689 hospitalizations, of which 4,661 (99.4%) had died or been discharged. The median age, and the proportion male or with any comorbidity decreased over time; median real-time PCR cycle threshold increased (indicating relatively less concentration of virus) (Table). For instance, median age decreased from 67 years in the first two weeks to 49 in the last two. Peak hospitalizations were during the fifth and sixth study weeks, which accounted for 40% of the hospitalizations. Median length of stay for patients who died or were discharged to hospice was 8 days (interquartile range, 4-16). Unadjusted mortality dropped each period, from 30.2% in the first two weeks to 3% in the last two weeks, with the last eight weeks being lower than the 95% control limits. Risk adjustment partially attenuated the mortality decline, but adjusted mortality rates in the second-to-last two weeks remained outside the control limits (Figure, Table). The O/E risk of mortality decreased from 1.07 (0.64-1.67) in the first two weeks to 0.39 (0.08-1.12) in the last two weeks. Discussion In this 16-week study of Covid-19 mortality at a single health system, we found that changes in demographics and severity of illness at presentation account for some, but not all, of the decrease in unadjusted mortality. Even after risk adjustment for a variety of clinical and demographic factors, mortality was significantly lower towards the end of the study period. Incremental improvements in outcomes are likely a combination of increasing clinical experience, decreasing hospital volume, growing use of new pharmacologic treatments (such as corticosteroids, remdesivir and anti-cytokine treatments), non-pharmacologic treatments (such as proning), earlier intervention, community awareness, and lower viral load exposure from increasing mask wearing and social distancing. It is also possible that earlier periods had a more virulent circulating strain. In summary, data from one health system suggest that Covid-19 remains a serious disease for high risk patients, but that outcomes may be improving.

ObjectiveTo describe demographics, causative pathogens, hospitalization, mortality, and antimicrobial resistance of bacterial bloodstream infections (BSIs) among beneficiaries in the global U.S. Military Health System (MHS), a single-provider healthcare system with 10-year longitudinal follow-up. DesignRetrospective cohort study SettingClinical and demographic data collected from the MHS Data Repository and collated with microbiological data obtained from the Defense Centers for Public Health-Portsmouth. Participants12,748 MHS beneficiaries diagnosed with 15,357 bacterial BSIs (2010-2019). Main Outcome(s) and Measure(s)Demographic data and diagnosis codes preceding BSI episodes and during hospitalizations were collected. Inpatient admission data identified acute clinical diagnoses, intensive care unit (ICU) admission, and mortality. BSI pathogens were evaluated for antimicrobial resistance, including difficult-to-treat resistance (DTR). Crude mortality trends were assessed. ResultsThe decade analyzed included 15,357 BSI episodes in 12,748 patients; 6,216 patients (48.8%) were [&ge;]65 years and 83.7% of episodes had [&ge;]1 comorbidity (12,856 of 15,357). Approximately 29% of episodes with hospitalization required ICU admission and [~]34% had concurrent urinary tract infections. Pathogen distribution was 53% and 47% for Gram-positive bacteria and Gram-negative bacilli (GNB), respectively. Inpatient mortality was 4.4%, and at one year was 23.4%; 0.5% (16 of 2,977) of deaths were associated with DTR GNB. Among an average 8,145,778 individuals receiving care annually in the MHS, annual rates of overall BSI, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and DTR GNB BSI were 18.9, 1.30, 0.25, and 0.05 per 100,000 beneficiaries, respectively. Over the decade, annual mortality did not significantly increase for any pathogen and decreased by [~]3% for lactose-fermenting GNB BSI (p=0.048). ConclusionsIn the global U.S. MHS, mortality burden associated with BSI was substantial (approximately 1 in 4 dying at 1 year), relatively unchanged over a decade, and associated with older age and comorbidities. First-line treatment options remained available for 99.7% of BSIs. Population-level improvements in BSI survival might be maximally influenced by focusing on prevention, early detection, prompt antibiotics, and other novel therapies not contingent on in vitro activity. Summary BoxWhat is already known on this topic: O_LIBloodstream infections (BSIs) are associated with high healthcare burden and poor patient outcomes, including high mortality. C_LIO_LIModeling data based on assumptions suggest that mortality associated with antimicrobial-resistant pathogens is increasing. C_LI What this study adds: O_LIAmong Military Health System (MHS) beneficiaries, overall and difficult-to-treat antimicrobial-resistant BSIs averaged an annual rate of 18.9 and 0.05 per 100,000 beneficiaries, respectively. C_LIO_LIOver a decade, mortality did not increase annually for any BSI group, while lactose-fermenting Gram-negative BSI mortality decreased ([~]3%) and 50% of BSIs associated with deaths at 1-year occurred >42 days after BSI diagnosis. C_LIO_LIBacterial BSI deaths in MHS are often associated with advanced age (74% [&ge;]65 years) and comorbidities (97% with [&ge;]1 comorbidity), rather than absence of first-line antimicrobial treatment options. C_LI

BackgroundRSV is a frequent cause of respiratory illness less often diagnosed outside hospital settings; thus, overall prevalence of RSV-associated illness is under-recognized. Information about presence of RSV among those with chronic conditions is especially needed with recent advances in vaccine development. MethodsParticipants prospectively enrolled in an ambulatory surveillance study of respiratory illness (MFIVE) were tested by RT-PCR for RSV and influenza. Participant and illness characteristics were collected by in-person survey and EMR review. Chronic conditions were characterized by the Multimorbidity-weighted index (MWI). Viral factors, including subtype and viral load, were compared between RSV-A and RSV-B. Multivariate logistic regression models were used to compare participant and illness characteristics between those with RSV and those with influenza. Comparisons were also made across RSV subtypes. ResultsAmong 4,442 individuals enrolled in MFIVE from fall 2017 to spring 2020, 9.9% (n=441) had RSV detected. RSV+ participants with increased viral load had increased odds of illness lasting [&ge;] 7 days [ORadj=2.39 (95% CI: 1.03-5.51) p-value=0.04]. Adults with RSV had higher median MWI scores compared to influenza and RSV/influenza-negative (1.62, 0.40, 0.64, respectively). ConclusionsOur findings support the need for ongoing RSV surveillance, particularly in older adults and those with multimorbidity. Our findings support a recognition of multimorbidity as a significant contributor to RSV-associated MAARI among outpatient adults, with particularly notable impacts among adults under 65.

BackgroundRespiratory syncytial virus (RSV) is an important cause of disease in older adults. Vaccines against RSV infections and respiratory diseases are in large market demand. Although there are currently two licensed RSV-based pre-F antigen vaccines available for older adults, no G antigen-based RSV vaccine is authorized. This phase 2 study aimed to evaluate the safety and immunogenicity of a recombinant G protein-based RSV vaccine in this population. MethodsA phase-2 randomized, double-blind, placebo-controlled, dose-ranging study was conducted to evaluate the safety, tolerability and immunogenicity of the BARS13 (rRSV G protein with CsA) when administered by an intramuscular (IM) injection to healthy participants 60 to 80 years old. A total of 125 eligible participants were randomized in a 3:1 ratio (vaccine versus placebo) for Cohorts 1 and 2 and randomized in a 2:1 ratio for Cohort 3 to receive one of the three treatment regimens or placebo. ResultsThe average age was 65.3, and 50.4% (63/125) were men. Until the interim analysis (4 weeks following the last vaccination), no treatment-related SAE occurred. TEAEs did not increase with vaccination dosage or frequency. All adverse effects were mild or moderate, not severe or life-threatening. BARS13 vaccination increased IgG anti-RSV antibody levels in all cohorts, but higher doses and frequency boosted immune responses significantly. The high-dose thrice-administered recipients had serum-specific IgG antibody GMC of 881.0 IU/mL (95% CI: 794.5-1473.4) before the first dose (Week 0), 1116.3 IU/mL (95% CI:990.7-1772.5) 4 weeks after the first dose (Week 4), 1309.4IU/mL (95% CI: 1162.8-2041.5) 4 weeks after the second dose (Week 8), and1359.6 IU/mL (95% CI: 1197.9-2525.7) 4 weeks after the third dose (Week 12). For the low-dose twice-administered recipients, 84% responded at 4 weeks after the first immunization (Week 4) and 83.3% at 4 weeks after the second (Week 8). The high-dose twice-administered recipients had 95.5% response at 4 weeks after the first immunization (Week 4) and 72.2% at 4 weeks after the second (Week 8). At Week 4, 85.7% of high-dose thrice-administered recipients responded, 85.2% at Week 8, and 79.2% at Week 12. ConclusionsThe study demonstrates the safety and tolerability of BARS13 across different dose groups. Adverse reactions were not significantly different among participants receiving varying doses of BARS13. Levels of anti-G antibodies exhibited a dose- and frequency-dependent responses in the older population. The continuous upward trend in antibody concentration up to the interim analysis is promising for the effectiveness of BARS13.

BackgroundRespiratory syncytial virus (RSV) is under-recognized in hospitalized adults. We evaluated severity of acute respiratory illness (ARI) including intensive care unit (ICU) admission and mechanical ventilation in a national surveillance network. MethodsHospitalized adults who met a standardized ARI case definition were prospectively enrolled across three respiratory seasons from hospitals participating across all sites of the U.S. Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN, 2016-2019). Multivariable logistic regression was used to test associations between lab-confirmed infection and characteristics and clinical outcomes. ResultsAmong 10,311 hospitalized adults, 6% tested positive for RSV (n=622), 18.8% positive for influenza (n=1,940), and 75.1% negative for RSV and influenza (n=7,749). The proportion of adults with Congestive Heart Failure (CHF) or Chronic Obstructive Pulmonary Disease (COPD) was higher among adults with RSV than influenza (CHF: 37.3% vs. 28.8%, p<0.0001; COPD: 47.6% vs. 35.8%, p<0.0001). Patients with RSV had higher odds of experiencing length of stay [&ge;]8 days [OR=1.38 (95% CI: 1.06-1.80), p-value=0.02] and invasive or noninvasive mechanical ventilation [OR=1.45 (95% CI: 1.09-1.93), p-value=0.01] compared with influenza patients. ConclusionsOur findings suggest patients with RSV might incur worse outcomes than influenza in hospitalized adults, who are likely to have pre-existing cardiopulmonary conditions.

BackgroundRespiratory Syncytial Virus (RSV) can cause severe respiratory disease. While risks among older adults are well established, less is known about RSV severity in younger adults with chronic conditions. MethodsA retrospective cohort study using U.S. commercial and Medicaid claims data was conducted to evaluate outcomes in adults aged 18-59 with medically attended RSV (MA-RSV) in 2022-24. Chronic conditions were assessed during a 12-month baseline period prior to the MA-RSV. Severe outcomes, including RSV-associated hospitalization, RSV-associated intensive care unit admission, mechanical ventilation, and death, were assessed within 30 days following RSV diagnosis. Adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) were estimated using multivariable models. ResultsIn both commercially insured (n=1435 in 2022-23; n=1890 in 2023-24) and Medicaid-insured (n=2065) adults with MA-RSV, approximately 75% had [&ge;]1 chronic condition, and over 25% had four or more. Severe RSV outcomes occurred in [~]21% of individuals. The risk of severe outcomes substantially increased with the number of chronic conditions. Among commercially insured adults, the aRR for those with two to three chronic conditions compared to none was 10.06 (95% CI: 4.80-21.08) in the 2022-2023 and 13.74 (95% CI: 5.95-31.73) in 2023-2024. For those with four or more conditions, the aRRs were 21.39 (95% CI: 10.26-44.60) and 38.03 (95% CI: 16.61-87.11), respectively. In the Medicaid cohort (2023-2024), the aRR was 7.68 (95% CI: 4.63-12.76) for individuals with two to three conditions and 13.85 (95% CI: 8.36- 22.95) for those with four or more. ConclusionAdults aged 18-59 years with chronic conditions are at increased risk for severe RSV illness, supporting broader prevention strategies, including vaccination.

ObjectivesTo determine the prevalence, clinical characteristics and outcomes of HIV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection. MethodsWe searched Medline, Embase, Cochrane and Web of Science databases and grey literature for studies reporting epidemiological and clinical data of patients with HIV and SARS-CoV-2 co-infection. Eligible studies were all observational or interventional studies and commentaries in English language that reported patient data on HIV/SARS-CoV-2 co-infection. We used random effect meta-analysis to determine the pooled prevalence and mortality. ResultsOf the 17 eligible studies, there were 3 retrospective cohorts, 1 survey, 5 case series, 7 case reports and 1 commentary that reported on a total of 146 HIV infected individuals. The pooled prevalence of HIV among individuals with SARS-CoV-2 infection was 1.0% (95% CI: 0.0 - 3.0, I2 = 79.3%, p = 0.01), whereas the prevalence of SARS-CoV-2 among HIV patients was 0.68% (95% CI: 0.34 - 1.34).There were 110 (83.8%) HIV/ SARS-CoV-2 co-infected males, and the age (range) of the co-infected was 30 - 60 years. A total of 129 (97.0%) were anti-retroviral therapy experienced, and 113 (85.6%) had a suppressed HIV viral load. The CD4 count (range) was 298 - 670 cells/mm3 (n = 107). The commonest symptoms were fever (73.5%, n = 75) and cough (57.8%, n = 59). Sixty-two (65.3%) patients had at least one other comorbid condition, of which hypertension (26.4%, n = 38) was the commonest. Chest radiological imaging abnormalities were found in 46 (54.1%) cases. Twenty-eight cases (56.0%) were reported as mild. Recovery occurred in 120 (88.9%) cases, and the pooled mortality was 9% (95% CI: 3.0 - 15.0, I2 = 25.6%, p = 0.24). ConclusionThe prevalence of HIV/SARS-CoV-2 co-infection was low. The clinical characteristics and outcomes of HIV/SARS-CoV-2 co-infection are comparable to those reported among HIV negative SARS-CoV-2 cases.

Background: In sub-Saharan Africa where both tuberculosis (TB) and HIV are prevalent, empiric TB treatment in people living with HIV (PLHIV) persists due to limited sensitivity of sputum-based TB tests. We evaluated mortality among molecular test-negative presumptive TB adult PLHIV in a population where the majority are or have been on antiretroviral therapy (ART), comparing mortality between those who received empiric TB treatment and those who did not. Materials and Methods: From November 2017 to December 2020, Xpert-negative presumptive TB adult PLHIV were recruited at Mulago Referral Hospital and Kisenyi Health Centre-IV in Kampala, Uganda. Clinical data including TB symptoms, chest X-ray, and empiric TB treatment decision were collected. Laboratory investigations included CD4 cell count, serum cryptococcal antigen (CrAg), urine TB-lipoarabinomannan (TB-LAM), microbiological blood cultures, and sputum mycobacterial growth indicator tube (MGIT) cultures. Participants were followed monthly for 12 months to ascertain vital status. Results: Overall, 300 participants were enrolled; 61.3% inpatients, 55.7% female, median age 37 (IQR 29-45) years, 82.3% on ART, median CD4 206 cells/mm3 (IQR 36-507). Of the 300 participants, 68 (22.7%) received empiric TB treatment, of which 53 (77.9%) were inpatients. 12-month mortality was 31.0% (93/300); 91.4% among inpatients, 72% within three months post-enrolment. Mortality was higher among those who received empiric TB treatment (51.5 vs. 30.2 per 1,000 person-months; p=0.013) compared to those who did not. TB cultures were positive in 5.0% (15/300), of whom seven (46.7%) were also TB-LAM positive. CrAg was positive in 12.3% and 3.7% had positive blood culture. Conclusion: We found high mortality among Xpert-negative PLHIV, particularly those who received empiric TB treatment, despite high ART coverage. Cryptococcal antigenemia and bacteremia were not uncommon. In presence of negative Xpert results in PLHIV, clinicians should perform extensive laboratory evaluations to identify possible comorbidities or alternative non-TB diagnosis.

BackgroundBroadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the only bnAb HIV prevention efficacy studies to date, the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. Greater efficacy is required before passively administered bnAbs become a viable option for HIV prevention; furthermore subcutaneous (SC) or intramuscular (IM) administration may be preferred. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. MethodsParticipants were recruited between 02 February 2018 and 09 October 2018. 124 healthy participants without HIV were randomized to receive five VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), SC (T4: 2.5 mg/kg, T5: 5 mg/kg) or IM (T6: 2.5 mg/kg or P6: placebo) routes at four-month intervals. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA after the first dose through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum pharmacokinetics. Neutralization activity was measured in a TZM-bl assay and anti-drug antibodies (ADA) were assayed using a tiered bridging assay testing strategy. ResultsInjections were well-tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusions were generally well-tolerated, with infusion reactions reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals) following the first administration were 29.0 g/mL (25.2, 33.4), 58.5 g/mL (49.4, 69.3), and 257.2 g/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 g/mL (8.8, 13.3) and 22.8 g/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 g/mL (14.7, 18.2) in T6 with IM dosing. Trough GM concentrations immediately prior to the second administration were 3.4 g/mL (2.5, 4.6), 6.5 g/mL (5.6, 7.5), and 27.2 g/mL (23.9, 31.0) with IV dosing; 0.97 g/mL (0.65, 1.4) and 3.1 g/mL (2.2, 4.3) with SC dosing, and 2.6 g/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titres, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titre ADA at a lone timepoint. VRC07-523LS has an estimated mean half-life of 42 days (95% CI: 40.5, 43.5), approximately twice as long as VRC01. ConclusionsVRC07-523LS was safe and well-tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens.

IntroductionHigh HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with severe Immune reconstitution inflammatory syndrome (S-IRIS-KS), which can occur after initiating cART, and is linked with high mortality particularly in patients with pulmonary involvement. We investigate if valganciclovir initiated before cART decreases HHV-8 VL and assess if it reduces the incidence of S-IRIS-KS and its attributable mortality. MethodsOpen-label parallel-group randomized clinical trial in AIDS cART naive patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node or gastrointestinal involvement, lymphedema, or [&ge;]30 skin lesions. In the experimental group (EG), patients were randomized to valganciclovir 900 mg BID four weeks before cART and continued until week-48; in the control group (CG), cART was initiated on week-0. Non-severe-IRIS-KS was defined as: increase in number of lesions plus [&ge;]one log10 HIV-VL decrease or [&ge;]50 cells/mm3 increase or [&ge;]2-fold rise in baseline CD4+cells. S-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia. Results40 patients were randomized and 37 completed the study. In the ITT analysis, the overall mortality did not differ between groups. In the per-protocol analyses, the difference showed a trend for higher S-IRIS-KS mortality in the CG 3/19 (15.7%), compared to EG 0/18 (p=0.07). The incidence of S-IRIS KS was significantly lower in the EG; two patients, one each had S-IRIS-KS episode (0.038 per 100 patient-days) compared to CG group, four patients developed 12 S-IRIS-KS episodes (0.21 per 100 patient-days); incidence rate of 0.09 (95% CI 0.02-0.5 p=0.006). Mortality in patients with pulmonary KS was significantly lower in EG, 3/4 in CG vs 0/5 in EG. S-IRIS-KS was associated with higher HHV-8-VL; IL6 and CRP; valganciclovir was protective. Of survivors at week 48, 82% achieved >80% remission. No difference was found between groups in the number of non-S-IRIS-KS events. ConclusionsValganciclovir significantly reduced the episodes of S-IRIS-KS although attributable KS mortality was lower in the EG the difference was not significant (p=0.07). Mortality was significantly lower in EG patients with pulmonary KS. NIH Clinical Trails ID NCT03296553.

IntroductionAn optimal vaginal microbiome is typically dominated by beneficial Lactobacillus species, whereas bacterial vaginosis (BV) is characterized by high microbial diversity and a paucity of vaginal lactobacilli. High recurrence rates of BV following antibiotic treatment may stem from poor recolonization by protective Lactobacillus species post-treatment. This has led to the hypothesis that live biotherapeutic interventions designed to promote Lactobacillus dominance could improve BV treatment outcomes. MethodsWe conducted a Phase I, double-blind, placebo-controlled randomized trial to evaluate two novel, vaginally delivered live biotherapeutic products (LBP), each containing multiple strains of Lactobacillus crispatus. The study was conducted at two sites: one in South Africa, and one in the United States. Eligible participants diagnosed with BV by Nugent score ([&ge;] 7) and Amsel criteria ([&ge;]3 out of 4 criteria), first received a course of oral metronidazole and were then randomized equally into one of five arms for 7 days of daily vaginal tablet use: a placebo, a 6-strain LBP (LC106), a 15-strain LBP (LC115), LC106 for 3 days followed by 4 days of placebo, or an unblinded overlap arm in which LC106 was initiated on day 3 of metronidazole treatment. The primary outcomes were safety and detection of any L. crispatus strains contained in the products, as determined by metagenomic sequencing within the first weeks of study participation. ResultsAcross all active arms combined, at least one LBP strain was detected in 66.1% (47/71) of participants at least once in the first five weeks of study participation. Among those with colonization in this period, nearly half (49%, 23/47) remained colonized with LBP strains at 12 weeks, demonstrating durable colonization despite a short initial treatment course. Colonization success was comparable across study arms and sites, although the study was not powered to detect small differences between arms. At both sites, participants were most often colonized by one of three component strains, with no geographic differences in strain colonization observed. Both LBP products were safe, acceptable and well tolerated, with no serious adverse events (AEs) reported. Local/genitourinary AEs occurred most often in the placebo arm. ConclusionIn this Phase 1 study of novel multi-strain L. crispatus LBPs, we demonstrated that the products were safe and acceptable, and established durable colonization after a short dosing course in geographically diverse populations. These results provide a foundation for the development of transformational interventions aimed at optimizing the vaginal microbiome.