Vaccine efficacy of ALVAC-HIV and bivalent subtype C gp120–MF59 in adults

BACKGROUND : A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox–protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1–2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa. METHODS : In this phase 2b–3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120–MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months. RESULTS : In January 2020, prespecified criteria for non-efficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month followup, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84). CONCLUSIONS : The ALVAC–gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity.Supported by grants (HHSN272201300033C and HHSN272201600012C) to Novartis Vaccines and Diagnostics (now part of the GlaxoSmithKline [GSK] Biologicals) by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) for the selection and process development of the two gp120 envelope proteins TV1.C and 1086.C; by the Bill and Melinda Gates Foundation Global Health Grant (OPP1017604) and NIAID for the manufacture and release of the gp120 clinical grade material; and by U.S. Public Health Service Grants — UM1 AI068614 to the HIV Vaccine Trials Network (HVTN), UM1 AI068635 to the HVTN Statistical and Data Management Center, and UM1 AI068618 to the HVTN Laboratory Center — from the NIAID. GSK Biologicals contributed financially to the provision of preexposure prophylaxis to trial participants. The South African Medical Research Council supported its affiliated research sites.http://www.nejm.orgam2022School of Health Systems and Public Health (SHSPH

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A Critical Evaluation of Validation and Clinical Experience Studies in Non-Invasive Prenatal Testing for Trisomies 21, 18, and 13 and Monosomy X

Non-invasive prenatal testing (NIPT) for trisomies 21, 18, 13 and monosomy X is widely utilized with massively parallel shotgun sequencing (MPSS), digital analysis of selected regions (DANSR), and single nucleotide polymorphism (SNP) analyses being the most widely reported methods. We searched the literature to find all NIPT clinical validation and clinical experience studies between January 2011 and January 2022. Meta-analyses were performed using bivariate random-effects and univariate regression models for estimating summary performance measures across studies. Bivariate meta-regression was performed to explore the influence of testing method and study design. Subgroup and sensitivity analyses evaluated factors that may have led to heterogeneity. Based on 55 validation studies, the detection rate (DR) was significantly higher for retrospective studies, while the false positive rate (FPR) was significantly lower for prospective studies. Comparing the performance of NIPT methods for trisomies 21, 18, and 13 combined, the SNP method had a higher DR and lower FPR than other methods, significantly so for MPSS, though not for DANSR. The performance of the different methods in the 84 clinical experience studies was consistent with validation studies. Clinical positive predictive values of all NIPT methods improved over the last decade. We conclude that all NIPT methods are highly effective for fetal aneuploidy screening, with performance differences across methodologies

Use of Donor-derived Cell-free DNA to Inform Tapering of Immunosuppression Therapy in Kidney Transplant Recipients: An Observational Study

Background. Immunosuppression therapy (IST) is required for allograft survival but can cause significant adverse effects. Donor-derived cell-free DNA (dd-cfDNA) is a validated noninvasive biomarker for active rejection in kidney transplant (KTx). Evidence supporting dd-cfDNA testing use in IST management is limited. Methods. In this single-center observational study, dd-cfDNA testing was performed in 21 KTx patients considered good candidates for mycophenolic acid (MPA) reduction. Patients with dd-cfDNA <1% at the first visit (enrollment) had their MPA dosage reduced; those with dd-cfDNA ≥1% had their MPA dosage maintained. Patients were monitored with dd-cfDNA for 6 additional visits. Results. Of 21 patients enrolled in the study, 17 were considered low risk for rejection by dd-cfDNA and underwent MPA reduction; 4 patients were considered high risk for rejection by dd-cfDNA and had their initial MPA dosage maintained. Of the 4 patients considered high risk for rejection by dd-cfDNA, 1 experienced chronic allograft nephropathy and graft loss, and another received an indication biopsy that showed no evidence of rejection. Of the 17 patients considered low risk for rejection by dd-cfDNA, none experienced allograft rejection. dd-cfDNA was used for surveillance in a 6-mo period following MPA reduction; no untoward results were noted. Conclusions. This proof-of-concept study reports the use of dd-cfDNA to directly inform IST management in a cohort of KTx who were candidates for IST reduction