RSV Prefusion F Protein-Based Maternal Vaccine - Preterm Birth and Other Outcomes.

BACKGROUND: Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed. METHODS: We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. The women were randomly assigned in a 2:1 ratio to receive RSVPreF3-Mat or placebo between 24 weeks 0 days and 34 weeks 0 days of gestation. The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract disease in infants from birth to 6 months of age and safety in infants from birth to 12 months of age. After the observation of a higher risk of preterm birth in the vaccine group than in the placebo group, enrollment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed. RESULTS: The analyses included 5328 pregnant women and 5233 infants; the target enrollment of approximately 10,000 pregnant women and their infants was not reached because enrollment was stopped early. A total of 3426 infants in the vaccine group and 1711 infants in the placebo group were followed from birth to 6 months of age; 16 and 24 infants, respectively, had any medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 65.5%; 95% credible interval, 37.5 to 82.0), and 8 and 14, respectively, had severe medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 69.0%; 95% credible interval, 33.0 to 87.6). Preterm birth occurred in 6.8% of the infants (237 of 3494) in the vaccine group and in 4.9% of those (86 of 1739) in the placebo group (relative risk, 1.37; 95% confidence interval [CI], 1.08 to 1.74; P = 0.01); neonatal death occurred in 0.4% (13 of 3494) and 0.2% (3 of 1739), respectively (relative risk, 2.16; 95% CI, 0.62 to 7.56; P = 0.23), an imbalance probably attributable to the greater percentage of preterm births in the vaccine group. No other safety signal was observed. CONCLUSIONS: The results of this trial, in which enrollment was stopped early because of safety concerns, suggest that the risks of any and severe medically assessed RSV-associated lower respiratory tract disease among infants were lower with the candidate maternal RSV vaccine than with placebo but that the risk of preterm birth was higher with the candidate vaccine. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT04605159.).

Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus Vaccine in Infants 6-7 Months of age: A Phase 1/2 Randomized Trial.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants. This phase 1/2, observer-blind, randomized, controlled study assessed the safety and immunogenicity of an investigational chimpanzee-derived adenoviral vector RSV vaccine (ChAd155-RSV, expressing RSV F, N, and M2-1) in infants. METHODS: Healthy 6- to 7-month-olds were 1:1:1-randomized to receive 1 low ChAd155-RSV dose (1.5 × 1010 viral particles) followed by placebo (RSV_1D); 2 high ChAd155-RSV doses (5 × 1010 viral particles) (RSV_2D); or active comparator vaccines/placebo (comparator) on days 1 and 31. Follow-up lasted approximately 2 years. RESULTS: Two hundred one infants were vaccinated (RSV_1D: 65; RSV_2D: 71; comparator: 65); 159 were RSV-seronaive at baseline. Most solicited and unsolicited adverse events after ChAd155-RSV occurred at similar or lower rates than after active comparators. In infants who developed RSV infection, there was no evidence of vaccine-associated enhanced respiratory disease (VAERD). RSV-A neutralizing titers and RSV F-binding antibody concentrations were higher post-ChAd155-RSV than postcomparator at days 31, 61, and end of RSV season 1 (mean follow-up, 7 months). High-dose ChAd155-RSV induced stronger responses than low-dose, with further increases post-dose 2. CONCLUSIONS: ChAd155-RSV administered to 6- to 7-month-olds had a reactogenicity/safety profile like other childhood vaccines, showed no evidence of VAERD, and induced a humoral immune response. Clinical Trials Registration. NCT03636906.

Association Between Hemagglutination Inhibition Antibody Titers and Protection Against Reverse-Transcription Polymerase Chain Reaction-Confirmed Influenza Illness in Children 6-35 Months of Age: Statistical Evaluation of a Correlate of Protection.

BACKGROUND: Data from a randomized controlled efficacy trial of an inactivated quadrivalent influenza vaccine in children 6-35 months of age were used to determine whether hemagglutination inhibition (HI) antibody titer against A/H1N1 and A/H3N2 is a statistical correlate of protection (CoP) for the risk of reverse-transcription polymerase chain reaction (RT-PCR)-confirmed influenza associated with the corresponding strain. METHODS: The Prentice criteria were used to statistically validate strain-specific HI antibody titer as a CoP. The probability of protection was identified using the Dunning model corresponding to a prespecified probability of protection at an individual level. The group-level protective threshold was identified using the Siber approach, leading to unbiased predicted vaccine efficacy (VE). A case-cohort subsample was used for this exploratory analysis. RESULTS: Prentice criteria confirmed that HI titer is a statistical CoP for RT-PCR-confirmed influenza. The Dunning model predicted a probability of protection of 49.7% against A/H1N1 influenza and 54.7% against A/H3N2 influenza at an HI antibody titer of 1:40 for the corresponding strain. Higher titers of 1:320 were associated with >80% probability of protection. The Siber method predicted VE of 61.0% at a threshold of 1:80 for A/H1N1 and 46.6% at 1:113 for A/H3N2. CONCLUSIONS: The study validated HI antibody titer as a statistical CoP, by demonstrating that HI titer is correlated with clinical protection against RT-PCR-confirmed influenza associated with the corresponding influenza strain and is predictive of VE in children 6-35 months of age. CLINICAL TRIALS REGISTRATION: NCT01439360.

Association of Group B Streptococcus (GBS) Serum Serotype-Specific Anticapsular Immunoglobulin G Concentration and Risk Reduction for Invasive GBS Disease in South African Infants: An Observational Birth-Cohort, Matched Case-Control Study.

BACKGROUND: Licensure of a group B Streptococcus (GBS) polysaccharide-protein conjugate vaccine for protecting infants against invasive GBS disease (IGbsD) will likely need to be based on demonstrating vaccine safety in pregnant women, and benchmarking immunogenicity against a serological threshold associated with risk reduction of IGbsD. We investigated the association between naturally derived GBS serotype Ia and III IgG and risk reduction of IGbsD in infants ≤90 days of age. METHODS: In a matched case-control study, IGbsD cases were identified from a cohort of 38 233 mother-newborn dyads. Mothers colonized vaginally with serotype Ia or III at birth and their healthy infants were eligible as matched controls. GBS serotype-specific anticapsular immunoglobulin G (IgG) was measured on maternal and cord blood/infant sera by multiplex Luminex assay, and the IgG threshold associated with 90% risk reduction of IGbsD was derived by estimating absolute disease risk. RESULTS: In infants born at ≥34 weeks' gestational age, cord-blood IgG geometric mean concentrations (GMCs) were lower in cases than controls for serotypes Ia (0.05 vs 0.50 µg/mL; P = .004) and III (0.20 vs 0.38 µg/mL; P = .078). Cord-blood IgG concentrations ≥1.04 and ≥1.53 µg/mL were associated with 90% risk reduction of serotype Ia and III IGbsD, respectively. The maternal sera IgG threshold associated with 90% risk reduction was ≥2.31 µg/mL and ≥3.41 µg/mL for serotypes Ia and III, respectively. CONCLUSIONS: The threshold associated with a reduced risk for serotype Ia and III IGbsD identified on infant sera supports the case for licensure of a GBS polysaccharide-protein conjugate vaccine based on an immunogenicity evaluation benchmarked against the defined thresholds. CLINICAL TRIALS REGISTRATION: NCT02215226.

MEDI0382, a GLP-1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, Phase 1 study.

AIMS: MEDI0382 is a balanced glucagon-like peptide-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus and non-alcoholic steatohepatitis. The primary objective was to assess the safety of MEDI0382 in healthy subjects. METHODS: In this placebo-controlled, double-blind, Phase 1 study, healthy subjects (aged 18-45 years) were randomized (3:1) to receive a single subcutaneous dose of MEDI0382 or placebo after ≥8 h of fasting. The study consisted of six cohorts that received study drug at 5 µg, 10 µg, 30 µg, 100 µg, 150 µg or 300 µg. The primary objective was safety and tolerability. Secondary endpoints included assessments of pharmacokinetics and immunogenicity. All subjects were followed for up to 28 days. RESULTS: A total of 36 subjects received MEDI0382 (n = 6 per cohort) and 12 subjects received placebo (n = 2 per cohort). Treatment-emergent adverse events (TEAEs) occurred more frequently with MEDI0382 vs. placebo, which was mostly due to an increased occurrence at MEDI0382 doses ≥150 µg. All TEAEs were mild or moderate in severity. The most common TEAEs were vomiting, nausea and dizziness. There appeared to be a dose-dependent increase in heart rate with MEDI0382 treatment. MEDI0382 showed linear pharmacokinetic profile (time to maximum plasma concentration: 4.50-9.00 h; elimination half-life: 9.54-12.07 h). No immunogenicity was observed in the study. CONCLUSIONS: In this single-dose, Phase 1 study in healthy subjects, the safety and pharmacokinetic profiles of MEDI0382 support once-daily dosing and further clinical development of MEDI0382.

Combined heart failure device diagnostics identify patients at higher risk of subsequent heart failure hospitalizations: results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) study.

OBJECTIVES: We sought to determine the utility of combined heart failure (HF) device diagnostic information to predict clinical deterioration of HF in patients with systolic left ventricular dysfunction. BACKGROUND: Some implantable devices continuously monitor HF device diagnostic information, but data are limited on the ability of combined HF device diagnostics to predict HF events. METHODS: The PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) was a prospective, multicenter observational study in patients receiving cardiac resynchronization therapy (CRT) implantable cardioverter-defibrillators. HF events were independently adjudicated. A combined HF device diagnostic algorithm was developed on an independent dataset. The algorithm was considered positive if a patient had 2 of the following abnormal criteria during a 1-month period: long atrial fibrillation duration, rapid ventricular rate during atrial fibrillation, high (> or =60) fluid index, low patient activity, abnormal autonomics (high night heart rate or low heart rate variability), or notable device therapy (low CRT pacing or implantable cardioverter-defibrillator shocks), or if they only had a very high (> or =100) fluid index. We used univariate and multivariable analyses to determine predictors of subsequent HF events within a month. RESULTS: We analyzed data from 694 CRT defibrillator patients who were followed for 11.7 +/- 2 months. Ninety patients had 141 adjudicated HF hospitalizations with pulmonary congestion at least 60 days after implantation. Patients with a positive combined HF device diagnostics had a 5.5-fold increased risk of HF hospitalization with pulmonary signs or symptoms within the next month (hazard ratio: 5.5, 95% confidence interval: 3.4 to 8.8, p < 0.0001), and the risk remained high after adjusting for clinical variables (hazard ratio: 4.8, 95% confidence interval: 2.9 to 8.1, p < 0.0001). CONCLUSIONS: Monthly review of HF device diagnostic data identifies patients at a higher risk of HF hospitalizations within the subsequent month. (PARTNERS HF: Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure; NCT00279955).

Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial.

OBJECTIVES: The purpose of this trial was to determine whether microvolt T-wave alternans (MTWA) predicts ventricular tachyarrhythmic events (VTEs) in post-myocardial infarction patients with left ventricular ejection fraction (LVEF) < or =30%. BACKGROUND: Previous studies have established MTWA as a predictor for total and arrhythmic mortality, but its ability to identify prophylactic implantable cardioverter-defibrillator (ICD) recipients most likely to experience VTEs remains uncertain. METHODS: This prospective trial was conducted at 50 U.S. centers. Patients were eligible if they met MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) indications for device implant. All patients underwent MTWA testing followed by ICD implantation, with pre-specified programming to minimize the likelihood of therapies for non-life-threatening VTE. Minimum follow-up was 2 years with annual MTWA testing. Initially indeterminate MTWA tests were repeated. RESULTS: Analyses were conducted on 575 patients (84% male; average age +/- SD = 65 +/- 11 years; average LVEF +/- SD = 0.24 +/- 0.05). The final distribution of MTWA results were: MTWA positive in 293 (51%), MTWA negative in 214 (37%), and indeterminate in 68 patients (12%). Over an average follow-up of 2.1 +/- 0.9 years, there were 70 VTEs. A VTE occurred in 48 of 361 (13%, 6.3%/year) MTWA non-negative and 22 of 214 (10%, 5.0%/year) MTWA negative patients. A non-negative MTWA test result was not associated with VTE (hazard ratio: 1.26; 95% confidence interval: 0.76 to 2.09; p = 0.37), although total mortality was significantly increased (hazard ratio: 2.04; 95% confidence interval: 1.10 to 3.78; p = 0.02). CONCLUSIONS: In MADIT-II-indicated ICD-treated patients, the risk of VTE does not differ according to MTWA classification, despite differences in total mortality. (MASTER I-Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients; NCT00305240).