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The randomized trial assessing the efficacy of a single injection of the Ad26.COV2.S showed 56.3% vaccine efficacy beginning 14 days after injection and 52.9% efficacy more than 28 days after injection against moderate to severe–critical Covid-19. Protection lasted at least 6 months without an added boost. Vaccination was associated with mild-to-moderate adverse effects.

We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306). Test of therapeutic mosaic vaccines in HIV-infected individuals shows no control of virus after treatment interruption.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe–critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe–critical COVID-19 was stable across most sequence features but lower against the most distant viruses. SARS-CoV-2 variants with mutations in spike have emerged during the pandemic. Magaret et al. show that in Latin America, efficacy of the Ad26.COV2.S vaccine against moderate to severe–critical COVID-19 varied by sequence features, antibody escape scores, and neutralization impacting features of the SARS-CoV-2 variant.

Antiretroviral agents active against drug-resistant HIV-1 are needed for treatment-experienced patients. The aim of this trial was to assess the efficacy, safety, and tolerability of TMC125 (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI). DUET-1 is a continuing, multinational randomised, double-blind, placebo-controlled, phase III trial. Treatment-experienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load over 5000 copies per mL, and three or more primary protease inhibitor mutations were randomly assigned to receive 200 mg TMC125 or placebo twice daily. All patients also received darunavir with low-dose ritonavir and investigator-selected nucleoside reverse transcriptase inhibitors. Enfuvirtide use was optional. The primary endpoint was a confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00254046. 612 patients were randomised and treated (304 in the TMC125 group, 308 in the placebo group). By week 24, 42 (14%) patients in the TMC125 group and 56 (18%) in the placebo group had discontinued, mainly due to virological failure. At week 24, 170 (56%) patients in the TMC125 group and 119 (39%) patients in the placebo group achieved a confirmed viral load of less than 50 copies per mL (difference in response rates 17%; 95% CI 9–25; p=0·005). Most adverse events were mild or moderate in severity. The type and incidence of adverse events, including neuropsychiatric events, seen with TMC125 were generally comparable with placebo, with the exception of rash (61 [20%] patients on TMC125 vs 30 [10%] on placebo) and diarrhoea (36 [12%] patients on TMC125 vs 63 [20%] on placebo). In treatment-experienced patients with NNRTI resistance, treatment with TMC125 achieved better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

TMC125 (etravirine) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with activity against NNRTI-resistant HIV-1 in phase IIb trials. The aim of DUET-2 is to examine the efficacy, tolerability, and safety of TMC125 in treatment-experienced patients. In this continuing randomised, double-blind, placebo-controlled, phase III trial, HIV-1-infected patients on failing antiretroviral therapy with evidence of resistance to currently available NNRTIs and at least three primary protease inhibitor mutations were eligible for enrolment if on stable (8 weeks unchanged) antiretroviral therapy with plasma HIV-1 RNA greater than 5000 copies per mL. Patients were randomly assigned to receive either TMC125 (200 mg) or placebo, each given twice daily with darunavir-ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors, and optional enfuvirtide. The primary endpoint was the proportion of patients with confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00255099. 591 patients were randomised and treated (295 patients in the TMC125 group and 296 in the placebo group). By week 24, 51 (17%) patients in the TMC125 group and 73 (25%) in the placebo group had discontinued, mainly because of virological failure. 183 (62%) patients in the TMC125 group and 129 (44%) in the placebo group achieved confirmed viral load below 50 copies per mL at week 24 (difference 18%, 95% CI 11–26; p=0·0003). The type and frequency of adverse events were much the same in the two groups. In treatment-experienced patients, treatment with TMC125 led to better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.

The global spread of the SARS-CoV-2 virus has resulted in emergence of lineages which impact the effectiveness of immunotherapies and vaccines that are based on the early Wuhan isolate. All currently approved vaccines employ the spike protein S, as it is the target for neutralizing antibodies. Here we describe two SARS-CoV-2 isolates with unusually large deletions in the N-terminal domain (NTD) of the spike. Cryo-EM structural analysis shows that the deletions result in complete reshaping of the NTD supersite, an antigenically important region of the NTD. For both spike variants the remodeling of the NTD negatively affects binding of all tested NTD-specific antibodies in and outside of the NTD supersite. For one of the variants, we observed a P9L mediated shift of the signal peptide cleavage site resulting in the loss of a disulfide-bridge; a unique escape mechanism with high antigenic impact. Although the observed deletions and disulfide mutations are rare, similar modifications have become independently established in several other lineages, indicating a possibility to become more dominant in the future. The observed plasticity of the NTD foreshadows its broad potential for immune escape with the continued spread of SARS-CoV-2.

Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. NCT02342249, 2014-004068-39, and CR107745.

Background JNJ-8678 is a RSV-specific fusion inhibitor and a potential new treatment for respiratory infections caused by RSV. Data from a Phase 1b study of PK, safety and antiviral effects in hospitalized RSV-infected infants are presented. Methods 37 and 7 patients, respectively, were randomized to JNJ-8678 (ascending doses, Table) or placebo (PBO) treatment once daily for 7 days. PK assessments were based on sparse sampling using a population PK model in adults scaled for pediatrics, accounting for allometric principles and maturation of drug clearance pathways. Safety was evaluated by AE reporting, lab and ECG assessments. Antiviral activity was assessed by measuring viral load (VL) using a quantitative RT-PCR assay for RSV RNA from nasal swabs. Results Sparse PK data are described by an integrated PK model (table) and indicated PK parameters for different dose levels were similar across age groups. Treatment with JNJ-8678 appeared to reduce VL more rapidly than PBO (figure). Median change in VL from baseline (BL) in JNJ-8678-treated patients (combined dose groups) vs. PBO was −1.98 vs. −0.32 log10 copies/mL at Day 3. Mean differences in change from BL (90% CI) of JNJ-8678 (combined dose groups) vs. PBO on Days 2 and 3 were estimated −1.33 (−2.26; −0.39) and −1.62 (−2.55; −0.69) log10 copies/mL, respectively (general linear model, adjusted for BL VL; P ≤ 0.05). There was a clear separation between JNJ-8678 and PBO, but no evident exposure–response relationship. JNJ-8678 was generally well tolerated with no new safety signals compared with adults and no dose relationship with AEs or lab abnormalities were observed. Conclusion This dataset in RSV-infected infants showed a clear trend for an early antiviral effect of JNJ-8678, which was similar across dose groups. JNJ-8678 treatment was generally well tolerated. Table: PK Data by Dose/Age Group Dose Dose (mg/kg) All n = 4 Age (Months) AUC24 Day 7, Mean ± SD Ctrough Day 7, Mean ± SD Low 1 1–3 5,121 ± 471 87 ± 16 1.5 3–6 6,236 ± 578 83 ± 18 2 6–24 5,631 ± 605 39 ± 14 Mid 3 1–3 17,867 ± 1,747 345 ± 64 4.5 3–6 21,965 ± 2,147 346 ± 73 6 6–24 19,693 ± 2,213 170 ± 60 Intermediate 8 6–24 27,454 ± 3,108 256 ± 88 High 5 1–3 32,478 ± 3,194 675 ± 120 6 3–6 30,722 ± 3,015 510 ± 105 9 6–24 31,445 ± 3,565 303 ± 103 Disclosures F. Martinon-Torres, Pfizer: Consultant, Consulting fee. SPMSD: Consultant, Consulting fee. GSK: Consultant, Consulting fee. S. Rusch, Janssen: Employee and Shareholder, Salary. D. Huntjens, Janssen: Employee and Shareholder, Salary. B. Remmerie, Janssen: Employee and Shareholder, Salary. J. Vingerhoets, Janssen: Employee and Shareholder, Salary. K. McFadyen, Janssen: Employee and Shareholder, Salary. E. Baraldi, Abbvie: Lectures, Speaker honorarium. Chiesi Farmaceutici: Consultant, Consulting fee. Novartis: Consultant, Consulting fee. Janssen: Consultant, Consulting fee. M. Stevens, Janssen: Employee and Shareholder, Salary.

The impact of baseline characteristics on response to the non-nucleoside reverse transcriptase inhibitor etravirine was investigated at 48 weeks in the Phase III DUET trials. Logistic regression was used to examine the effect of baseline demographics, disease characteristics and characteristics of antiretroviral therapy on virologic response (viral load <50 HIV-1 RNA copies/ml) to etravirine in pre-specified pooled subgroup analyses. Several nondemographic characteristics were significant predictors of response in univariate analyses. Baseline viral load, adherence to study medication and use of enfuvirtide were predictive of response in the multivariate analysis. Patients treated with etravirine consistently achieved higher response rates than placebo-treated patients. The clinical benefits of etravirine in the DUET trials were observed irrespective of baseline characteristics.