Gefapixant as a P2X3 receptor antagonist treatment for obstructive sleep apnea: a randomized controlled trial.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a highly prevalent disorder with serious health consequences but limited therapeutic options. For a subset of those with OSA, a key underlying mechanism is hypersensitive chemoreflex control of breathing. There is no approved therapy that targets this endotypic trait. Here we determine whether the P2X3 receptor antagonist gefapixant, which is predicted to attenuate hypersensitive carotid chemoreflexes, reduces OSA severity in patients with chemoreflex-dependent OSA. METHODS: In a randomized placebo-controlled cross-over study, 24 patients with moderate-to-severe OSA (aged 39-68 years, non-CPAP users) whose disorder was partially responsive to supplemental oxygen (chemoreflex-dependent OSA) were treated with gefapixant 180 mg (or placebo) administered as tablets taken orally before bedtime for 7 days and assessed via overnight polysomnography. The primary analysis examined whether gefapixant treatment resulted in a greater reduction in the apnea-hypopnea index (AHI) from baseline than placebo. RESULTS: Gefapixant did not lower the AHI significantly more than placebo; the estimated ratio of the AHI on gefapixant versus placebo was 0.92 [90% CI: 0.73, 1.17]. Notably, nocturnal hypoxemia was increased (ratio of total sleep time with SpO2 <90% on gefapixant versus placebo = 2.08 [90% CI: 1.53, 2.82]), consistent with reduced chemoreflex output. Commonly reported adverse events with gefapixant included ageusia, dysgeusia, oral hypoaesthesia, nausea, somnolence, and taste disorders. CONCLUSIONS: Gefapixant, while generally well tolerated, did not reduce OSA severity in patients with chemoreflex-dependent OSA. P2X3 receptor antagonism is unlikely to provide an avenue for therapeutic intervention in OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Safety and Tolerability of Gefapixant (MK-7264) in Participants With Obstructive Sleep Apnea (MK-7264-039); URL: https://clinicaltrials.gov/study/NCT03882801; Identifier: NCT03882801.

Safety and Immunogenicity of a Messenger RNA-Based Cytomegalovirus Vaccine in Healthy Adults: Results From a Phase 1, Randomized, Clinical Trial.

BACKGROUND: This phase 1 trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1647, an mRNA-based cytomegalovirus (CMV) vaccine, in CMV-seronegative and -seropositive adults. METHODS: Participants were randomly assigned to receive 30, 90, 180, or 300 µg of mRNA-1647 or placebo on a 0-, 2-, and 6-month schedule and followed for 12 months after the last dose. RESULTS: A total of 154 (80 CMV-seronegative and 74 CMV-seropositive) participants were enrolled; 118 participants were randomized to mRNA-1647 and 36 to placebo. Mean (SD) age was 32.5 (8.6) and 35.1 (8.9) years in the placebo and mRNA-1647 groups, respectively, in phase B (63% and 64% female) and 42.5 (6.2) and 33.3 (8.7) years, respectively, in phase C (2% and 16% female). No deaths, related serious adverse events, or adverse events of special interest were reported. Most adverse reactions were grade ≤2 severity. Increased neutralizing antibody, binding antibody, and antigen-specific cell-mediated responses were observed across mRNA-1647 treatment groups, regardless of CMV serostatus. CONCLUSIONS: This phase 1, first-in-human trial demonstrated mRNA-1647 has an acceptable safety profile in adults and elicits humoral and cellular immune responses. TRIALS REGISTRATION: NCT03382405; https://clinicaltrials.gov/ct2/show/NCT03382405.

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600-1,600 mg and after 14 daily doses of ≥95% at 50-200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .

Genome-Wide Association Study and Genomic Prediction of Fusarium Wilt Resistance in Common Bean Core Collection.

The common bean (Phaseolus vulgaris L.) is a globally cultivated leguminous crop. Fusarium wilt (FW), caused by Fusarium oxysporum f. sp. phaseoli (Fop), is a significant disease leading to substantial yield loss in common beans. Disease-resistant cultivars are recommended to counteract this. The objective of this investigation was to identify single nucleotide polymorphism (SNP) markers associated with FW resistance and to pinpoint potential resistant common bean accessions within a core collection, utilizing a panel of 157 accessions through the Genome-wide association study (GWAS) approach with TASSEL 5 and GAPIT 3. Phenotypes for Fop race 1 and race 4 were matched with genotypic data from 4740 SNPs of BARCBean6K_3 Infinium Bea Chips. After ranking the 157-accession panel and revealing 21 Fusarium wilt-resistant accessions, the GWAS pinpointed 16 SNPs on chromosomes Pv04, Pv05, Pv07, Pv8, and Pv09 linked to Fop race 1 resistance, 23 SNPs on chromosomes Pv03, Pv04, Pv05, Pv07, Pv09, Pv10, and Pv11 associated with Fop race 4 resistance, and 7 SNPs on chromosomes Pv04 and Pv09 correlated with both Fop race 1 and race 4 resistances. Furthermore, within a 30 kb flanking region of these associated SNPs, a total of 17 candidate genes were identified. Some of these genes were annotated as classical disease resistance protein/enzymes, including NB-ARC domain proteins, Leucine-rich repeat protein kinase family proteins, zinc finger family proteins, P-loopcontaining nucleoside triphosphate hydrolase superfamily, etc. Genomic prediction (GP) accuracy for Fop race resistances ranged from 0.26 to 0.55. This study advanced common bean genetic enhancement through marker-assisted selection (MAS) and genomic selection (GS) strategies, paving the way for improved Fop resistance.

Safety and immunogenicity of a phase 1/2 randomized clinical trial of a quadrivalent, mRNA-based seasonal influenza vaccine (mRNA-1010) in healthy adults: interim analysis.

Despite vaccine availability, influenza remains a substantial global public health concern. Here, we report interim findings on the primary and secondary objectives of the safety, reactogenicity, and humoral immunogenicity of a quadrivalent messenger RNA (mRNA) vaccine against seasonal influenza, mRNA-1010, from the first 2 parts of a 3-part, first-in-human, phase 1/2 clinical trial in healthy adults aged ≥18 years (NCT04956575). In the placebo-controlled Part 1, a single dose of mRNA-1010 (50 µg, 100 µg, or 200 µg) elicited hemagglutination inhibition (HAI) titers against vaccine-matched strains. In the active-comparator-controlled Part 2, mRNA-1010 (25 µg, 50 µg, or 100 µg) elicited higher HAI titers than a standard dose, inactivated seasonal influenza vaccine for influenza A strains and comparable HAI titers for influenza B strains. No safety concerns were identified; solicited adverse reactions were dose-dependent and more frequent after receipt of mRNA-1010 than the active comparator. These interim data support continued development of mRNA-1010.

Bivalent Omicron BA.1-Adapted BNT162b2 Booster in Adults Older than 55 Years.

BACKGROUND: The emergence of immune-escape variants of severe acute respiratory syndrome coronavirus 2 warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019. METHODS: In an ongoing phase 3 trial, adults older than 55 years who had previously received three 30-µg doses of the BNT162b2 vaccine were randomly assigned to receive 30 µg or 60 µg of BNT162b2, 30 µg or 60 µg of monovalent B.1.1.529 (omicron) BA.1-adapted BNT162b2 (monovalent BA.1), or 30 µg (15 µg of BNT162b2 + 15 µg of monovalent BA.1) or 60 µg (30 µg of BNT162b2 + 30 µg of monovalent BA.1) of BA.1-adapted BNT162b2 (bivalent BA.1). Primary objectives were to determine superiority (with respect to 50% neutralizing titer [NT50] against BA.1) and noninferiority (with respect to seroresponse) of the BA.1-adapted vaccines to BNT162b2 (30 µg). A secondary objective was to determine noninferiority of bivalent BA.1 to BNT162b2 (30 µg) with respect to neutralizing activity against the ancestral strain. Exploratory analyses assessed immune responses against omicron BA.4, BA.5, and BA.2.75 subvariants. RESULTS: A total of 1846 participants underwent randomization. At 1 month after vaccination, bivalent BA.1 (30 µg and 60 µg) and monovalent BA.1 (60 µg) showed neutralizing activity against BA.1 superior to that of BNT162b2 (30 µg), with NT50 geometric mean ratios (GMRs) of 1.56 (95% confidence interval [CI], 1.17 to 2.08), 1.97 (95% CI, 1.45 to 2.68), and 3.15 (95% CI, 2.38 to 4.16), respectively. Bivalent BA.1 (both doses) and monovalent BA.1 (60 µg) were also noninferior to BNT162b2 (30 µg) with respect to seroresponse against BA.1; between-group differences ranged from 10.9 to 29.1 percentage points. Bivalent BA.1 (either dose) was noninferior to BNT162b2 (30 µg) with respect to neutralizing activity against the ancestral strain, with NT50 GMRs of 0.99 (95% CI, 0.82 to 1.20) and 1.30 (95% CI, 1.07 to 1.58), respectively. BA.4-BA.5 and BA.2.75 neutralizing titers were numerically higher with 30-µg bivalent BA.1 than with 30-µg BNT162b2. The safety profile of either dose of monovalent or bivalent BA.1 was similar to that of BNT162b2 (30 µg). Adverse events were more common in the 30-µg monovalent-BA.1 (8.5%) and 60-µg bivalent-BA.1 (10.4%) groups than in the other groups (3.6 to 6.6%). CONCLUSIONS: The candidate monovalent or bivalent omicron BA.1-adapted vaccines had a safety profile similar to that of BNT162b2 (30 µg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA.5, and BA.2.75 strains. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04955626.).

Intranasal M2SR (M2-Deficient Single Replication) H3N2 Influenza Vaccine Provides Enhanced Mucosal and Serum Antibodies in Adults.

BACKGROUND: We previously demonstrated that an intranasal dose of 108 50% tissue culture infectious dose (TCID50) M2-deficient single replication (M2SR) influenza vaccine protected against highly drifted H3N2 influenza challenge in a subset of subjects who demonstrated ≥2-fold increase in microneutralization (MN) antibodies to Belgium2015 (the challenge strain) after vaccination. Here, we describe a phase 1b, observer-blinded, dose-escalation study demonstrating an increased proportion of responders with this signal of immune protection. METHODS: Serosusceptible subjects aged 18-49 years were randomized to receive 2 doses (108-109 TCID50) of M2SR or placebo administered 28 days apart. Clinical specimens were collected before and after each dose. The primary objective was to demonstrate safety of M2SR vaccines. RESULTS: The vaccine was well tolerated at all dose levels. Against Belgium2015, ≥ 2-fold increases in MN antibodies were noted among 40% (95% confidence interval [CI], 24.9%-56.7%) of subjects following a single 108 TCID50 M2SR dose and among 80.6% (95% CI, 61.4%-92.3%) after 109 dose (P < .001). A single 109 TCID50 dose of M2SR generated ≥4-fold hemagglutination inhibition antibody seroconversion against the vaccine strain in 71% (95% CI, 52.0%-85.8%) of recipients. Mucosal and cellular immune responses were also induced. CONCLUSIONS: These results indicate that M2SR may provide substantial protection against infection with highly drifted strains of H3N2 influenza. CLINICAL TRIALS REGISTRATION: NCT03999554.

In recent years, influenza A H3N2 viruses have evolved into multiple cocirculating clades, resulting in low vaccine efficacy and highlighting the need for more effective influenza vaccines. In a previous challenge study, a single intranasal dose of the investigational vaccine M2SR demonstrated protection against a highly drifted H3N2 influenza challenge virus in a subset of vaccine recipients with a signature immune response. Increasing the dose of the M2SR vaccine in this phase1b study demonstrated a statistically significant increase in the proportion of subjects with the signature immune responses seen previously. The vaccine-induced antibodies were cross-reactive with a panel of drifted H3N2 viruses from 2007 to 2019. Additionally, M2SR generated a rise in serum hemagglutination inhibition antibody titer in 71% of subjects. In contrast, the H3N2 seroresponse rate for the licensed intranasal vaccine FluMist is 10% in seronegative adults. Moreover, M2SR elicited mucosal and cell-mediated immune responses. This study demonstrates that the intranasal M2SR generates a multifaceted immune response and has the potential to provide better efficacy against vaccine-matched strains and influenza drift variants reducing the need to update the vaccine on an annual basis. This is a noteworthy step in the development of a broadly protective influenza vaccine.

Genome-Wide Association Study and Genomic Prediction for Bacterial Wilt Resistance in Common Bean (Phaseolus vulgaris) Core Collection.

Common bean (Phaseolus vulgaris) is one of the major legume crops cultivated worldwide. Bacterial wilt (BW) of common bean (Curtobacterium flaccumfaciens pv. flaccumfaciens), being a seed-borne disease, has been a challenge in common bean producing regions. A genome-wide association study (GWAS) was conducted to identify SNP markers associated with BW resistance in the USDA common bean core collection. A total of 168 accessions were evaluated for resistance against three different isolates of BW. Our study identified a total of 14 single nucleotide polymorphism (SNP) markers associated with the resistance to BW isolates 528, 557, and 597 using mixed linear models (MLMs) in BLINK, FarmCPU, GAPIT, and TASSEL 5. These SNPs were located on chromosomes Phaseolus vulgaris [Pv]02, Pv04, Pv08, and Pv09 for isolate 528; Pv07, Pv10, and Pv11 for isolate 557; and Pv04, Pv08, and Pv10 for isolate 597. The genomic prediction accuracy was assessed by utilizing seven GP models with 1) all the 4,568 SNPs and 2) the 14 SNP markers. The overall prediction accuracy (PA) ranged from 0.30 to 0.56 for resistance against the three BW isolates. A total of 14 candidate genes were discovered for BW resistance located on chromosomes Pv02, Pv04, Pv07, Pv08, and Pv09. This study revealed vital information for developing genetic resistance against the BW pathogen in common bean. Accordingly, the identified SNP markers and candidate genes can be utilized in common bean molecular breeding programs to develop novel resistant cultivars.

Safety and Immunogenicity of a 100 µg mRNA-1273 Vaccine Booster for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2).

Importance: Due to the emergence of highly transmissible SARS-CoV-2 variants, evaluation of boosters is needed. Objectives: Evaluate safety and immunogenicity of 100-µg of mRNA-1273 booster dose in adults. Design: Open-label, Phase 2/3 study. Setting: Multicenter study at 8 sites in the U.S. Participants: The mRNA-1273 100-µg booster was administered to adults who previously received a two dose primary series of 100-µg mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier. Intervention: Lipid nanoparticle containing 100-µg of mRNA encoding the spike glycoprotein of SARS-CoV-2 (Wuhan-HU-1). Main Outcomes and Measures: Solicited local and systemic adverse reactions, and unsolicited adverse events were collected after vaccination. Primary immunogenicity objectives were to demonstrate non-inferiority of the neutralizing antibody (nAb) response against SARS-CoV-2 based on the geometric mean titer (GMTs) and the seroresponse rates (SRRs) (booster dose vs. primary series in a historical control group). nAbs against SARS-CoV-2 variants were also evaluated. Results: The 100-µg booster dose had a greater incidence of local and systemic adverse reactions compared to the second dose of mRNA-1273 as well as the 50-µg mRNA-1273 booster in separate studies. The geometric mean titers (GMTs; 95% CI) of SARS-CoV-2 nAbs against the ancestral SARS-CoV-2 at 28 days after the 100-µg booster dose were 4039.5 (3592.7,4541.8) and 1132.0 (1046.7,1224.2) at 28 days after the second dose in the historical control group [GMT ratio=3.6 (3.1,4.2)]. SRRs (95% CI) were 100% (98.6,100) at 28 days after the booster and 98.1% (96.7,99.1) 28 days after the second dose in the historical control group [percentage difference=1.9% (0.4,3.3)]. The GMT ratio (GMR) and SRR difference for the booster as compared to the primary series met the pre-specified non-inferiority criteria. Delta-specific nAbs also increased (GMT fold-rise=233.3) after the 100-µg booster of mRNA-1273. Conclusions and Relevance: The 100-µg mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2, and reactogenicity was higher with the 100-µg booster dose compared to the authorized booster dose level in adults (50-µg). mRNA-1273 100-µg booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts. Trial Registration: NCT04927065.

Safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, administered concomitantly with influenza vaccine in healthy adults aged ≥50 years: a randomized phase 3 trial (PNEU-FLU).

Streptococcus pneumoniae and influenza viruses are associated with significant morbidity and mortality in older adults. Concomitant vaccination against these agents reduces hospitalization and mortality rates. This phase 3 trial evaluated safety, tolerability, and immunogenicity of concomitant and non-concomitant administration of V114, a 15-valent pneumococcal conjugate vaccine containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 22F, 23F, 33F, and quadrivalent inactivated influenza vaccine (QIV), in healthy adults aged ≥50 years. Participants (N = 1,200) were randomized 1:1 to receive either V114 administered concomitantly with QIV (concomitant group) or QIV plus placebo (non-concomitant group) on Day 1, followed by placebo (concomitant group) or V114 (non-concomitant group) 30 days later. Randomization was stratified by age and history of pneumococcal polysaccharide vaccine receipt. Overall, 426 (71.0%) and 438 (73.5%) participants in the concomitant and non-concomitant groups experienced solicited injection-site adverse events (AEs); 278 (46.3%) and 300 (50.3%) reported solicited systemic AEs. Most solicited AEs were mild or moderate in severity and of short duration. Non-inferiority for pneumococcal- and influenza-specific antibody responses (lower bound 95% confidence interval of opsonophagocytic activity [OPA] and hemagglutination inhibition geometric mean titers [GMTs] ratios ≥0.5) was demonstrated for concomitant versus non-concomitant administration for all 15 pneumococcal serotypes and all four influenza strains. Consistent with previous studies, a trend was observed toward lower pneumococcal OPA GMTs in the concomitant versus the non-concomitant group. V114 administered concomitantly with QIV is generally well tolerated and immunologically non-inferior to non-concomitant administration, supporting coadministration of both vaccines.

A phase 3 trial of safety, tolerability, and immunogenicity of V114, 15-valent pneumococcal conjugate vaccine, compared with 13-valent pneumococcal conjugate vaccine in adults 50 years of age and older (PNEU-AGE).

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have greatly reduced the incidence of pneumococcal disease, yet unmet medical need remains due to increased disease caused by non-vaccine serotypes (STs). V114 (VAXNEUVANCETM, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) is a 15-valent PCV containing 13 serotypes in licensed PCV13 and 2 additional serotypes (22F, 33F) which significantly contribute to pneumococcal disease burden. This phase 3 trial compared safety, tolerability, and immunogenicity of V114 to PCV13 in adults ≥50 years of age. METHODS: Adults were randomized 1:1 to receive a single dose of V114 or PCV13; randomization was stratified by age (50-64 years, 65-74 years, and ≥75 years). Adverse events (AEs) were collected following vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were measured prior to and 30 days after vaccination (Day 30). Primary objectives included assessing noninferiority of V114 to PCV13 for the 13 shared serotypes and superiority of V114 to PCV13 for the two unique serotypes. Superiority of V114 to PCV13 for shared serotype 3 was assessed as a secondary objective. RESULTS: Overall, 1,202 participants were vaccinated (V114 N = 602, PCV13 N = 600). The most commonly reported AEs across both groups were injection-site pain, fatigue, and myalgia. V114 met noninferiority criteria compared to PCV13 for the 13 shared serotypes (using a 2-fold non-inferiority margin for the ratio of OPA geometric mean titers [GMTs] [V114/PCV13] at Day 30) and met superiority for the 2 unique serotypes (using a 2-fold super-superiority margin for the ratio of OPA GMTs [V114/PCV13] at Day 30 and a 0.10 super-superiority margin for the difference in proportions of participants with ≥4-fold rise from prevaccination to Day 30). V114 met superiority criteria compared to PCV13 for serotype 3 (based on a super-superiority margin of 1.2 for the ratio of the OPA GMTs [V114/PCV13] and a superiority margin of 0 for the difference in proportions of participants with ≥4-fold rise). [NCT03950622, EudraCT#2018-004316-22, Japic-CTI#194845].

Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1-2, dose-ranging study.

BACKGROUND: CoV2 preS dTM is a stabilised pre-fusion spike protein vaccine produced in a baculovirus expression system being developed against SARS-CoV-2. We present interim safety and immunogenicity results of the first-in-human study of the CoV2 preS dTM vaccine with two different adjuvant formulations. METHODS: This phase 1-2, randomised, double-blind study is being done in healthy, SARS-CoV-2-seronegative adults in ten clinical research centres in the USA. Participants were stratified by age (18-49 years and ≥50 years) and randomly assigned using an interactive response technology system with block randomisation (blocks of varying size) to receive one dose (on day 1) or two doses (on days 1 and 22) of placebo or candidate vaccine, containing low-dose (effective dose 1·3 µg) or high-dose (2·6 µg) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline) or unadjuvanted high-dose antigen (18-49 years only). Primary endpoints were safety, assessed up to day 43, and immunogenicity, measured as SARS-C0V-2 neutralising antibodies (geometric mean titres), assessed on days 1, 22, and 36 serum samples. Safety was assessed according to treatment received in the safety analysis set, which included all randomly assigned participants who received at least one dose. Neutralising antibody titres were assessed in the per-protocol analysis set for immunogenicity, which included participants who received at least one dose, met all inclusion and exclusion criteria, had no protocol deviation, had negative results in the neutralisation test at baseline, and had at least one valid post-dose serology sample. This planned interim analysis reports data up to 43 days after the first vaccination; participants in the trial will be followed up for 12 months after the last study injection. This trial is registered with ClinicalTrials.gov, NCT04537208, and is ongoing. FINDINGS: Between Sept 3 and Sept 29, 2020, 441 individuals (299 aged 18-49 years and 142 aged ≥50 years) were randomly assigned to one of the 11 treatment groups. The interim safety analyses included 439 (>99%) of 441 randomly assigned participants (299 aged 18-49 years and 140 aged ≥50 years). Neutralising antibody titres were analysed in 326 (74%) of 441 participants (235 [79%] of 299 aged 18-49 years and 91 [64%] of 142 aged ≥50 years). There were no vaccine-related unsolicited immediate adverse events, serious adverse events, medically attended adverse events classified as severe, or adverse events of special interest. Among all study participants, solicited local and systemic reactions of any grade after two vaccine doses were reported in 81% (95% CI 61-93; 21 of 26) of participants in the low-dose plus AF03 group, 93% (84-97; 74 of 80) in the low-dose plus AS03 group, 89% (70-98; 23 of 26) in the high-dose plus AF03 group, 95% (88-99; 81 of 85) in the high-dose plus AS03 group, 29% (10-56; five of 17) in the unadjuvanted high-dose group, and 21% (8-40; six of 29) in the placebo group. A single vaccine dose did not generate neutralising antibody titres above placebo levels in any group at days 22 or 36. Among participants aged 18-49 years, neutralising antibody titres after two vaccine doses were 13·1 (95% CI 6·40-26·9) in the low-dose plus AF03 group, 20·5 (13·1-32·1) in the low-dose plus AS03 group, 43·2 (20·6-90·4) in the high-dose plus AF03 group, 75·1 (50·5-112·0) in the high-dose plus AS03 group, 5·00 (not calculated) in the unadjuvanted high-dose group, and 5·00 (not calculated) in the placebo group. Among participants aged 50 years or older, neutralising antibody titres after two vaccine doses were 8·62 (1·90-39·0) in the low-dose plus AF03 group, 12·9 (7·09-23·4) in the low-dose plus AS03 group, 12·3 (4·35-35·0) in the high-dose plus AF03 group, 52·3 (25·3-108·0) in the high-dose plus AS03 group, and 5·00 (not calculated) in the placebo group. INTERPRETATION: The lower than expected immune responses, especially in the older age groups, and the high reactogenicity after dose two were probably due to higher than anticipated host-cell protein content and lower than planned antigen doses in the formulations tested, which was discovered during characterisation studies on the final bulk drug substance. Further development of the AS03-adjuvanted candidate vaccine will focus on identifying the optimal antigen formulation and dose. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. RESULTS: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

Common bean varieties demonstrate differential physiological and metabolic responses to the pathogenic fungus Sclerotinia sclerotiorum.

Plant physiology and metabolism are important components of a plant response to microbial pathogens. Physiological resistance of common bean (Phaseolus vulgaris L.) to the fungal pathogen Sclerotinia sclerotiorum has been established, but the mechanisms of resistance are largely unknown. Here, the physiological and metabolic responses of bean varieties that differ in physiological resistance to S. sclerotiorum are investigated. Upon infection, the resistant bean variety A195 had a unique physiological response that included reduced photosynthesis and maintaining a higher leaf surface pH during infection. Leaf metabolomics was performed on healthy tissue adjacent to the necrotic lesion at 16, 24, and 48 hr post inoculation, and 144 metabolites were detected that varied between A195 and Sacramento following infection. The metabolites that varied in leaves included amines/amino acids, organic acids, phytoalexins, and ureides. The metabolic pathways associated with resistance included amine metabolism, uriede-based nitrogen remobilization, antioxidant production, and bean-specific phytoalexin production. A second experiment was conducted in stems of 13 bean genotypes with varying resistance. Stem resistance was associated with phytoalexin production, but unlike leaf metabolism, lipid changes were associated with susceptibility. Taken together, the data supports a multifaceted, physiometabolic response of common bean to S. sclerotiorum that mediates resistance.

MALDI-TOF-MS with PLS Modeling Enables Strain Typing of the Bacterial Plant Pathogen Xanthomonas axonopodis.

Matrix-assisted desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) is a fast and effective tool for microbial species identification. However, current approaches are limited to species-level identification even when genetic differences are known. Here, we present a novel workflow that applies the statistical method of partial least squares discriminant analysis (PLS-DA) to MALDI-TOF-MS protein fingerprint data of Xanthomonas axonopodis, an important bacterial plant pathogen of fruit and vegetable crops. Mass spectra of 32 X. axonopodis strains were used to create a mass spectral library and PLS-DA was employed to model the closely related strains. A robust workflow was designed to optimize the PLS-DA model by assessing the model performance over a range of signal-to-noise ratios (s/n) and mass filter (MF) thresholds. The optimized parameters were observed to be s/n = 3 and MF = 0.7. The model correctly classified 83% of spectra withheld from the model as a test set. A new decision rule was developed, termed the rolled-up Maximum Decision Rule (ruMDR), and this method improved identification rates to 92%. These results demonstrate that MALDI-TOF-MS protein fingerprints of bacterial isolates can be utilized to enable identification at the strain level. Furthermore, the open-source framework of this workflow allows for broad implementation across various instrument platforms as well as integration with alternative modeling and classification algorithms. Graphical abstract ᅟ.

Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults.

MEDI4893 is an investigational immunoglobulin G1(κ) monoclonal antibody that specifically binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. A triple-amino-acid substitution, M252Y/S254T/T256E, was engineered into the MEDI4893 Fc region to extend its serum half-life. A phase 1, double-blind, dose escalation study was designed to evaluate the safety, tolerability, pharmacokinetics, anti-alpha-toxin-neutralizing activity, and antidrug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18 to 65 years of age. Thirty-three subjects were randomly assigned to receive MEDI4893 at 225 mg (n = 3), 750 mg (n = 3), 2,250 mg (n = 8), or 5,000 mg (n = 12) or placebo (n = 7) and were followed for 360 days. Adverse events were mild or moderate in severity; none were serious. The MEDI4893 peak serum concentration increased dose proportionally from 77.2 µg/ml (225-mg dose) to 1,784 µg/ml (5,000-mg dose). The area under the concentration-time curve from 0 to 360 days also increased dose proportionally, from 4,840 µg · day/ml (225-mg dose) to 91,493 µg · day/ml (5,000-mg dose), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated to be 80 to 112 days, which is approximately 4-fold longer than the half-lives of other human immunoglobulin G antibodies. The alpha-toxin-neutralizing activity in serum correlated highly with the MEDI4893 concentrations in serum. Three adults transiently tested positive for ADA on day 151, but this did not have an impact on MEDI4893 serum concentrations or the MEDI4893 safety profile; no subjects exhibited serum ADA at the study end. These data support the continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia. (This study has been registered at ClinicalTrials.gov under identifier NCT02296320.).

Next-day residual effects of gabapentin, diphenhydramine, and triazolam on simulated driving performance in healthy volunteers: a phase 3, randomized, double-blind, placebo-controlled, crossover trial.

OBJECTIVE: Next-day residual effects of a nighttime dose of gabapentin 250 mg were evaluated on simulated driving performance in healthy participants in a randomized, placebo-controlled, double-blind, multicenter, four-period crossover study that included diphenhydramine citrate 76 mg and triazolam 0.5 mg. METHODS: At treatment visits, participants (n = 59) were dosed at ~23:30, went to bed immediately, and awakened 6.5 h postdose for evaluation. The primary endpoint was the standard deviation of lateral position for the 100-km driving scenario. Additional measures of driving, sleepiness, and cognition were included. RESULTS: Study sensitivity was established with triazolam, which demonstrated significant next-day impairment on all driving endpoints, relative to placebo (p < 0.001). Gabapentin demonstrated noninferiority to placebo on standard deviation of lateral position and speed deviation but not for lane excursions. Diphenhydramine citrate demonstrated significant impairment relative to gabapentin and placebo on speed deviation (p < 0.05). Other comparisons were either nonsignificant or statistically ineligible per planned, sequential comparisons. Secondary endpoints for sleepiness and cognitive performance were supportive of these conclusions. CONCLUSIONS: Together, these data suggest that low-dose gabapentin had no appreciable next-day effects on simulated driving performance or cognitive functioning. Copyright © 2016 John Wiley & Sons, Ltd.

Daclatasvir + asunaprevir + beclabuvir ± ribavirin for chronic HCV genotype 1-infected treatment-naive patients.

BACKGROUND AND AIMS: This phase-2b study examined the safety and efficacy of an all-oral, interferon-free combination of the NS5A replication complex inhibitor daclatasvir (DCV), the NS3 protease inhibitor asunaprevir (ASV), and the nonnucleoside NS5B polymerase inhibitor beclabuvir (BCV) with or without ribavirin in patients with HCV genotype (GT) 1 infection. METHODS: A total of 187 patients received 12 weeks of DCV 30 mg BID plus ASV 200 mg BID and BCV 150 mg BID (n = 86) or 75 mg BID with (n = 21) or without (n = 80) weight-based ribavirin BID. The primary endpoint was HCV RNA <25 IU/ml at post-treatment week 12 (SVR12). RESULTS: Overall, 90% of patients (169/187) in the combined treatment groups achieved SVR on or after post-treatment week 12. SVR rates were similar across subgroups (by mITT analysis), i.e. patients with cirrhosis (88%, 14/16), HCV GT-1a (90%, 137/155), and IL28B non-CC genotype (90%, 115/128). There were no drug-related serious AEs or grade 4 AEs. The most frequently reported AEs were headache, diarrhoea, fatigue and nausea. Addition of ribavirin to DCV+ASV+BCV was associated with decreased haemoglobin, compared with DCV+ASV+BCV alone. There were six grade 3/4 laboratory abnormalities noted, all unrelated to the study drugs. Viral breakthrough occurred in 2.5-4.8% of patients across groups and appeared unrelated to BCV dose or ribavirin inclusion. CONCLUSIONS: Results support phase 3 evaluation of a twice-daily, fixed-dose formulation of this DCV+ASV+BCV regimen with or without ribavirin in HCV GT-1-infected patients.

A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy.

BACKGROUND AND AIMS: Remimazolam is an ultra-short-acting benzodiazepine currently being developed for procedural sedation and for induction and maintenance of anesthesia. This trial was the fourth study for procedural sedation. The aim was to compare the safety and efficacy profile of remimazolam and to refine suitable doses for subsequent phase III studies in this indication. METHODS: This was a randomized, double-blind, parallel group, active controlled clinical trial with 162 male and female patients, aged 18 to 70, scheduled to undergo a routine colonoscopy. Patients were randomized to receive 1 of 3 remimazolam doses or midazolam for sedation. Supplemental oxygen and 100 µg of fentanyl was given before procedures were started, and the colonoscopy commenced as soon as suitable sedation had been achieved (Modified Observer's Assessment of Alertness/Sedation score ≤3). Top-up doses of the study drug and/or fentanyl were allowed to maintain suitable sedation and/or analgesia. Response was defined as sufficient sedation, no rescue sedative, and no ventilation required. RESULTS: This study showed that a single dose of remimazolam or midazolam, followed by top-up doses to maintain suitable sedation, provided adequate sedation with a high success rate (>92%) for the remimazolam groups, compared with 75% for the midazolam group (P = .007). There was no requirement for mechanical ventilation in any group, and procedure failures were all due to use of rescue sedative. CONCLUSIONS: The high success rates and good safety profile of remimazolam observed in this study warrants further investigation and confirmation in phase III trials. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01145222.).