Safety, tolerability, and immunogenicity of the Ebola Sudan chimpanzee adenovirus vector vaccine (cAd3-EBO S) in healthy Ugandan adults: a phase 1, open-label, dose-escalation clinical trial.

BACKGROUND: Sudan Ebola virus can cause severe viral disease, with an average case fatality rate of 54%. A recent outbreak of Sudan Ebola virus in Uganda caused 55 deaths among 164 confirmed cases in the second half of 2022. Although vaccines and therapeutics specific for Zaire Ebola virus have been approved for use during outbreak situations, Sudan Ebola virus is an antigenically distinct virus with no approved vaccines available. METHODS: In this phase 1, open-label, dose-escalation trial we evaluated the safety, tolerability, and immunogenicity of a monovalent chimpanzee adenovirus 3 vaccine against Sudan Ebola virus (cAd3-EBO S) at Makerere University Walter Reed Project in Kampala, Uganda. Study participants were recruited from the Kampala metropolitan area using International Review Board-approved written and electronic media explaining the trial intervention. Healthy adults without previous receipt of Ebola, Marburg, or cAd3 vectored-vaccines were enrolled to receive cAd3-EBO S at either 1 × 1010 or 1 × 1011 particle units (PU) in a single intramuscular vaccination and were followed up for 48 weeks. Primary safety and tolerability endpoints were assessed in all vaccine recipients by reactogenicity for the first 7 days, adverse events for the first 28 days, and serious adverse events throughout the study. Secondary immunogenicity endpoints included evaluation of binding antibody and T-cell responses against the Sudan Ebola virus glycoprotein, and neutralising antibody responses against the cAd3 vector at 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT04041570, and is completed. FINDINGS: 40 healthy adults were enrolled between July 22 and Oct 1, 2019, with 20 receiving 1 × 1010 PU and 20 receiving 1 × 1011 PU of cAd3-EBO S. 38 (95%) participants completed all follow-up visits. The cAd3-EBO S vaccine was well tolerated with no severe adverse events. The most common reactogenicity symptoms were pain or tenderness at the injection site (34 [85%] of 40), fatigue (29 [73%] of 40), and headache (26 [65%] of 40), and were mild to moderate in severity. Positive responses for glycoprotein-specific binding antibodies were induced by 2 weeks in 31 (78%) participants, increased to 34 (85%) participants by 4 weeks, and persisted to 48 weeks in 31 (82%) participants. Most participants developed glycoprotein-specific T-cell responses (20 [59%, 95% CI 41-75] of 34; six participants were removed from the T cell analysis after failing quality control parameters) by 4 weeks after vaccination, and neutralising titres against the cAd3 vector were also increased from baseline (90% inhibitory concentration of 47, 95% CI 30-73) to 4 weeks after vaccination (196, 125-308). INTERPRETATION: The cAd3-EBO S vaccine was safe at both doses, rapidly inducing immune responses in most participants after a single injection. The rapid onset and durability of the vaccine-induced antibodies make this vaccine a strong candidate for emergency deployment in Sudan Ebola virus outbreaks. FUNDING: National Institutes of Health via interagency agreement with Walter Reed Army Institute of Research.

Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial.

BACKGROUND: Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS. METHODS: VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332. FINDINGS: Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection. INTERPRETATION: CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Effect of a Chikungunya Virus-Like Particle Vaccine on Safety and Tolerability Outcomes: A Randomized Clinical Trial.

Importance: Chikungunya virus (CHIKV) is a mosquito-borne Alphavirus prevalent worldwide. There are currently no licensed vaccines or therapies. Objective: To evaluate the safety and tolerability of an investigational CHIKV virus-like particle (VLP) vaccine in endemic regions. Design, Setting, and Participants: This was a randomized, placebo-controlled, double-blind, phase 2 clinical trial to assess the vaccine VRC-CHKVLP059-00-VP (CHIKV VLP). The trial was conducted at 6 outpatient clinical research sites located in Haiti, Dominican Republic, Martinique, Guadeloupe, and Puerto Rico. A total of 400 healthy adults aged 18 through 60 years were enrolled after meeting eligibility criteria. The first study enrollment occurred on November 18, 2015; the final study visit, March 6, 2018. Interventions: Participants were randomized 1:1 to receive 2 intramuscular injections 28 days apart (20 µg, n = 201) or placebo (n = 199) and were followed up for 72 weeks. Main Outcomes and Measures: The primary outcome was the safety (laboratory parameters, adverse events, and CHIKV infection) and tolerability (local and systemic reactogenicity) of the vaccine, and the secondary outcome was immune response by neutralization assay 4 weeks after second vaccination. Results: Of the 400 randomized participants (mean age, 35 years; 199 [50%] women), 393 (98%) completed the primary safety analysis. All injections were well tolerated. Of the 16 serious adverse events unrelated to the study drugs, 4 (25%) occurred among 4 patients in the vaccine group and 12 (75%) occurred among 11 patients in the placebo group. Of the 16 mild to moderate unsolicited adverse events that were potentially related to the drug, 12 (75%) occurred among 8 patients in the vaccine group and 4 (25%) occurred among 3 patients in the placebo group. All potentially related adverse events resolved without clinical sequelae. At baseline, there was no significant difference between the effective concentration (EC50)-which is the dilution of sera that inhibits 50% infection in viral neutralization assay-geometric mean titers (GMTs) of neutralizing antibodies of the vaccine group (46; 95% CI, 34-63) and the placebo group (43; 95% CI, 32-57). Eight weeks following the first administration, the EC50 GMT in the vaccine group was 2005 (95% CI, 1680-2392) vs 43 (95% CI, 32-58; P < .001) in the placebo group. Durability of the immune response was demonstrated through 72 weeks after vaccination. Conclusions and Relevance: Among healthy adults in a chikungunya endemic population, a virus-like particle vaccine compared with placebo demonstrated safety and tolerability. Phase 3 trials are needed to assess clinical efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT02562482.

Diagnostic value of NT-proBNP in identifying impaired coronary flow reserve in asymptomatic moderate or severe aortic stenosis.

AIM: NT-proBNP has been shown to be a reliable biochemical marker for left ventricular wall stress. The relationship between NT-proBNP and coronary flow reserve (CFR) was evaluated in patients with significant asymptomatic aortic stenosis (AS). METHODS: A total of 74 patients with moderate or severe AS, mean age 66.68 ± 10.02 years (56.75% males), were enrolled in this prospective study. All patients underwent coronary angiography and had no obstructive coronary disease (defined as having no stenosis >50% in diameter). They had all undergone standard transthoracic Doppler-echo study and adenosine stress transthoracic-echo for CFR measurement and laboratory analysis for NT-proBNP measurement. RESULTS: The median NT-proBNP value was significantly increased (417.0 pg/ml; interquartile range [IQR]: 176.8-962.2 pg/ml). NT-proBNP was significantly higher in the group with CFR ≤2.5 (median: 549.0 pg/ml; IQR: 311.5-1131.0 pg/ml; as opposed to median: 291.5 pg/ml; IQR: 123.0-636.2 pg/ml; W = 452; p = 0.012). NT-proBNP showed significant negative correlation with CFR (ρ = -0.377, p = 0.001). There was also significant correlation between NT-proBNP and E/E´, S´ and aortic valve resistance. The NT-proBNP value of 334.00 pg/ml was determined as the best cut-off value for the diagnosis of CFR ≤2.5 (area under the curve: 0.67; 95%CI: 0.54-0.79; p < 0.01) and the sensitivity and specificity were 74 and 64%, respectively. CONCLUSION: Elevated NT-proBNP can indicate patients with impaired CFR in asymptomatic moderate or severe AS patients with preserved ejection fraction and nonobstructive coronary arteries.

Impact of hospital-acquired Clostridium difficile.

BACKGROUND AND AIM: To investigate the impact of hospital-acquired Clostridium difficile infection (CDI) on hospital costs and patient length of stay. METHODS: Data from the 2007-2008 New York State Department of Health's Statewide Planning and Research Cooperative System (SPARCS) database was analyzed using regression analysis and descriptive statistics. RESULTS: After analysis of 4 853 800 patient discharges, the incidence rate of hospital-acquired CDI was 0.8 cases per 1000 discharges. The estimated marginal cost associated with each hospital infection was approximately $29 000. The estimated annual cost of CDI in New York State was approximately $55 million with nearly 23 000 additional hospital days. CONCLUSIONS: The development of hospital-acquired CDI is associated with a significant increase in hospital costs and patient length of stay. Extrapolation of these estimates to all US hospitals suggests this condition represents a major burden to the US healthcare system. Our findings may help hospitals understand the impact of these infections, as well as potential implications if deemed preventable by Centers for Medicare & Medicaid Services and/or private payers. Additionally, this information may benefit hospitals or health care systems transitioning to alternative payment models, such as episode-based payments or accountable care. Healthcare providers and hospitals would benefit from better understanding the impact and frequency of these infections in order to best target preventive strategies.

The financial impact of hospital-acquired conditions.

CONTEXT: This article investigates the financial impact of the Centers for Medicare & Medicaid Services' hospital-acquired conditions (HACs). METHODS: Data from 2007-2008 was analyzed using New York State Department of Health's Statewide Planning and Research Cooperative System (SPARCS), using regression analysis and descriptive statistics for each condition. RESULTS: Of 4,853,800 patient discharges, the development of decubitus ulcers was the most prevalent condition, associated with an annual cost of nearly $680 million and 376,546 hospital days. Mediastinitis after Coronary Artery Bypass Graft (CABG) had the highest marginal impact for both length of stay (LOS) and total costs, but this condition had a relatively low frequency. Extrapolation of the results suggests that HACs represent a major burden to US hospitals. CONCLUSIONS: HACs have a significant financial impact on the US health care system. Hospitals would benefit from better understanding the impact and frequency of these conditions in order to best target preventative strategies.

Coronary flow reserve in patients with aortic stenosis and nonobstructed coronary arteries.

OBJECTIVE: Patients with moderate and severe aortic stenosis (AS) and without obstructive epicardial coronary disease have been shown to have an impairment of coronary flow velocity reserve (CFVR). Recently, it has been shown that CFVR is an independent predictor for future cardiovascular events in AS patients. We investigated parameters representing left ventricular (LV) mass and wall thickness, diastolic dysfunction, LV workload and haemodynamic indexes of AS severity to determine which contributes the most to impaired CFVR in patients with AS and a nonobstructed coronary angiogram. METHOD AND RESULTS: A total of 77 patients with moderate or severe AS, mean age 65.66 +/- 11.02 y (57.14% males), were enrolled in this prospective study. All patients had standard Doppler-echo study, coronary angiography and adenosine-stress transthoracic Doppler-echo for CFVR measurement. We took 2.5 as a cut-off value for impaired CFVR. Univariate analysis showed that aortic valve area (AVA), maximal velocity (Vmax), mean pressure gradient (Pmean), energy loss index (ELI), aortic valve resistance (AVR) and stroke work loss (SWL) were associated (P = 0.05) with impaired CFVR. Multivariate analysis showed that AVR was the best predictor of impaired CFVR (RR 0.900, Cl: 0.983-0.997, P = 0.007). Using ROC analysis, the AVR value of 211.22 dynes x s x cm(-5) had the highest accuracy in predicting the impaired CFVR (AUC-0.681, P=0.007, sensitivity 72%, specificity 52%, CI: 0.561-0.800). CONCLUSION: Haemodynamic indices of AS severity, together with LV workload parameters, are the main determinants of CFVR. Among all parameters, AVR is the strongest predictor of CFVR in patients with moderate or severe AS and a nonobstructed coronary angiogram.

Development and validation of a patient self-assessment score for diabetes risk.

BACKGROUND: National guidelines disagree on who should be screened for undiagnosed diabetes. No existing diabetes risk score is highly generalizable or widely followed. OBJECTIVE: To develop a new diabetes screening score and compare it with other available screening instruments (Centers for Disease Control and Prevention, American Diabetes Association, and U.S. Preventive Services Task Force guidelines; 2 American Diabetes Association risk questionnaires; and the Rotterdam model). DESIGN: Cross-sectional data. SETTING: NHANES (National Health and Nutrition Examination Survey) 1999 to 2004 for model development and 2005 to 2006, plus a combined cohort of 2 community studies, ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study), for validation. PARTICIPANTS: U.S. adults aged 20 years or older. MEASUREMENTS: A risk-scoring algorithm for undiagnosed diabetes, defined as fasting plasma glucose level of 7.0 mmol/L (126 mg/dL) or greater without known diabetes, was developed in the development data set. Logistic regression was used to determine which participant characteristics were independently associated with undiagnosed diabetes. The new algorithm and other methods were evaluated by standard diagnostic and feasibility measures. RESULTS: Age, sex, family history of diabetes, history of hypertension, obesity, and physical activity were associated with undiagnosed diabetes. In NHANES (ARIC/CHS), the cut-point of 5 or more points selected 35% (40%) of persons for diabetes screening and yielded a sensitivity of 79% (72%), specificity of 67% (62%), positive predictive value of 10% (10%), and positive likelihood ratio of 2.39 (1.89). In contrast, the comparison scores yielded a sensitivity of 44% to 100%, specificity of 10% to 73%, positive predictive value of 5% to 8%, and positive likelihood ratio of 1.11 to 1.98. LIMITATION: Data during pregnancy were not available. CONCLUSION: This easy-to-implement diabetes screening score seems to demonstrate improvements over existing methods. Studies are needed to evaluate it in diverse populations in real-world settings. PRIMARY FUNDING SOURCE: Clinical and Translational Science Center at Weill Cornell Medical College.

Economic impact of hyponatremia in hospitalized patients: a retrospective cohort study.

BACKGROUND: Hyponatremia is the most common electrolyte abnormality seen in general hospital patients, with an incidence of 1% to 6% in the United States. OBJECTIVE: We aimed to evaluate the impact of varying levels of hyponatremia at admission on length of stay (LOS) and cost of care in adult hospitalized patients. METHODS: A retrospective cohort study was conducted using an existing clinical database from a large academic-setting hospital. All adult admissions from January 2004 through May 2005 with serum sodium level at admission of < or = 134 mEq/L were separated into 2 cohorts: patients with moderate-to-severe hyponatremia (serum sodium level at admission of < or = 129 mEq/L, n = 547) and patients with mild-to-moderate hyponatremia (serum sodium level of 130-134 mEq/L, n = 1500). ICD-9 diagnosis codes for these 2047 admissions with hyponatremia were used to identify a cohort of 7573 admissions with the same principal admitting diagnoses and a serum sodium level of 135 to 145 mEq/L. Differences in hospital LOS, intensive care unit (ICU) admission rate, and median total costs per admission between cohorts were examined using multiple linear regression, logistic, and quantile regression models. RESULTS: Admissions with hyponatremia had significantly longer hospital LOS than those admitted without hyponatremia (median LOS: moderate-to-severe hyponatremia, 8 days; mild-to-moderate hyponatremia, 8 days; normal, 6 days; P < 0.001). Patients with more severe hyponatremia were also more likely to be admitted to the ICU during the hospital stay (moderate-to-severe hyponatremia, 32%; mild-to-moderate hyponatremia, 26%; normal, 22%; P < 0.001). These trends were also reflected in the total costs per admission, with median costs of $16,606 for moderate-to-severe hyponatremia cases, $14,266 for mild-to-moderate hyponatremia cases, and $13,066 for normal admissions (P < 0.001). CONCLUSIONS: Hyponatremia at admission was associated with increased LOS and cost of care for hospitalized patients. Interventions or pharmacotherapies for the prompt treatment of hyponatremia could potentially reduce morbidity and LOS, thereby reducing the utilization of health care resources.