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In an efficacy trial, 2504 persons at high risk for HIV-1 acquisition received either a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine or placebo. The vaccine regimen did not reduce either HIV-1 acquisition or viral load. The epidemic infection caused by the human immunodeficiency virus type 1 (HIV-1) is now in its fourth decade, with an estimated 2.5 million new infections occurring annually worldwide. 1 The number of newly infected persons, although diminishing, outpaces the number of patients who initiate antiretroviral therapy. Despite a number of successful prevention interventions that have been reported, including preexposure prophylaxis and treatment as prevention, 2 – 9 ultimate control of the HIV epidemic will most likely come only with the development of a safe and effective preventive vaccine. This goal has proved to be elusive. Of the efficacy trials of HIV vaccines that . . .

Unlike the response to many viral infections, most people do not produce antibodies capable of clearing HIV-1. Non-neutralizing antibodies that target HIV-1's envelope glycoprotein (Env) typically dominate the response, which is generated by B cells that cross-react with Env and the intestinal microbiota. Williams et al. analyzed samples from individuals who had received a vaccine containing the Env protein, including the gp41 subunit. Most of the antibodies were non-neutralizing and targeted gp41. The antibodies also reacted to intestinal microbiota, suggesting that preexisting immunity to microbial communities skews vaccineinduced immune responses toward an unproductive target. Science , this issue 10.1126/science.aab1253 . The antibody response to an HIV-1 vaccine is dominated by preexisting immunity to microbiota. An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1–reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1–reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.

The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean. 480 participants were evenly randomized to receive either: DNA (4 mg i.m. by Biojector) at 0, 1 and 2 months, followed by rAd5 (10(10) PU i.m. by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost. The vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%-94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients. The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies. ClinicalTrials.gov NCT00125970.

Introduction Antiretroviral therapy (ART) prevents and treats, but does not eradicate, HIV. Early ART initiation is associated with post‐ART virologic control, particularly among African women, and anti‐HIV‐1 broadly neutralizing antibodies (bnAbs) may modulate immune responses to HIV. We evaluate whether early ART with or without anti‐HIV‐1 bnAb VRC01, present at HIV acquisition, is associated with later ART‐free control in African women and we assess potential associations with observed control. Methods Stakeholder engagement informed analytical treatment interruption (ATI) study design and implementation. Participants who received placebo or VRC01 and acquired HIV in the Antibody Mediated Prevention efficacy trial were assessed for ATI eligibility, including HIV acquisition within 8 weeks of receiving VRC01 or placebo, followed by early ART initiation and ≥1 year of viral suppression. Participation facilitators and barriers were assessed. From May 2021 to February 2024, participants enrolled, stopped ART and received frequent viral load and CD4+ T‐cell count monitoring for safety and assessment of meeting ART reinitiation criteria. Results Thirteen women enrolled from southern Africa. No ATI‐related serious adverse events (AEs), HIV transmissions, pregnancies or ≥Grade 2 AEs were observed. Eight sexually transmitted infections were diagnosed in seven women during ATI. Two participants had tenofovir levels consistent with use during ATI; 2/11 (18%) who completed ATI without antiretroviral use exhibited ART‐free control for ≥32 weeks. The median time to confirmed VL≥200 was 5.4 weeks (range 2.7−112). The most common ART reinitiation criterion met was virologic (n = 7). VRC01 receipt proximate to HIV acquisition was not associated with control. Controllers versus non‐controllers did not differ by early post‐acquisition viral load kinetics, acquired virus characteristics, or time from estimated acquisition to closest infusion or to ART initiation. Conclusions In a safe, well‐tolerated ATI, 18% of 11 African women exhibited post‐intervention control. Design and implementation lessons inform future ATIs in Africa. Analyses of peri‐acquisition and post‐ATI host and viral characteristics can inform the development of interventions for HIV cure, prevention and treatment. Clinical Trial Registration NCT04860323

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HIV disproportionately impacts transgender populations globally, creating challenges to inclusion in trials requiring low HIV risk profiles (LHRP) for acquisition. Our knowledge of transgender individuals with LHRP is limited. We conducted an analysis of transgender and cisgender individuals in HVTN trials enrolling individuals with LHRP. We analyzed data from 694 participants enrolled in the phase 1-2a HVTN trials in the US and Peru from 2009 to 2014 that included individuals who reported gender identity (GI) differing from assigned birth sex (transgender [TG]), and compared them with those who reported a congruent GI (cisgender [CG]). 681 participants (98%) were CG and 13 (2%) were TG. Mean age was 25 years. 16% were Hispanic and most (69%) were White. Reasons for enrolling included to help find an effective vaccine (TG 100%; CG 98%) and help their community (TG 100%; CG 96%). Significant differences by GI were observed in reported pre-existing conditions (p = 0.004); however, approximately 10% of pre-existing conditions reported by TG were GI-related (e.g., gender dysphoria). Significant differences were observed in hormone therapy use (p < 0.001) and mental health medications (p = 0.007). Retention was excellent with 2.1% missed visits and no discontinuations of vaccination for TG and 3% missed visits and 7.1% discontinuations among CG. There was no statistically significant difference in HIV incidence. Primary reasons for participation were altruistic for all participants. Comparable to CG counterparts, TG participants maintained LHRP, followed trial procedures, and had high retention, facilitating meaningful early phase HIV preventive vaccine trial contributions.

In South Africa, HIV acquisition risk has been studied less in people assigned male at birth. We studied the associations between risk behaviors, clinical features and HIV incidence amongst males in two South African HIV preventive vaccine efficacy trials. We used Cox proportional hazards models to test for associations between demographics, sexual behaviors, clinical variables and HIV acquisition among males followed in the HVTN 503 (n = 219) and HVTN 702 (n = 1611) trials. Most males reported no male sexual partners (99.09% in HVTN 503) or identified as heterosexual (88.08% in HVTN 702). Annual HIV incidence was 1.39% in HVTN 503 (95% CI 0.76–2.32%) and 1.33% in HVTN 702 (95% CI 0.80–2.07%). Increased HIV acquisition was significantly associated with anal sex (HR 6.32, 95% CI 3.44–11.62), transactional sex (HR 3.42, 95% CI 1.80–6.50), and non-heterosexual identity (HR 16.23, 95%CI 8.13–32.41) in univariate analyses and non-heterosexual identity (HR 14.99, 95% CI 4.99–45.04; p < 0.01) in multivariate analysis. It is appropriate that prevention efforts in South Africa, although focused on the severe epidemic in young women, also encompass key male populations, including men who have sex with men, but also men who engage in anal or transactional sex.

This IBM Redbooks publication is a practical guide to developing Web applications using WebSphere Studio. WebSphere Studio is used to develop a sample Web application targeted to the WebSphere Application Server - Express runtime platform. It implements a sample scenario based on realistic requirements for small and medium customers, and provides an end-to-end guide for the development of this scenario.The book focuses on describing a simple process that allows non technical readers to understand and participate in the development of Web applications using WebSphere Studio .Part 1 of the book is an overview of the Web application development process and the tools available within WebSphere Studio.Part 2 describes the requirements and design of a sample application and details the process, architecture, and tools used to develop that sample. It is a detailed explanation of the steps needed to build the sample application. This illustrates how to achieve areas of functionality commonly found in dynamic Web applications, and provides worked examples that new developers can use in their own applications.Please note that the additional material referenced in the text is not available from IBM.

This IBM Redbooks publication is a practical guide for developing Web applications using the Rational Software Development Platform. We use the Rational Web Developer development environment that is provided as part of WebSphere Application Server - Express V6 to develop a sample Web application targeted to the WebSphere Application Server - Express runtime platform. We discuss a sample scenario based on realistic requirements for small and medium customers, and provide a guide for the development of this scenario. Our focus is on describing a simple process that allows non technical readers to understand and participate in the development of Web applications using Rational Web Developer. Our target runtime environment is the Express Application Server so we use the Rational Web Developer development environment that is part of the WebSphere Application Server - Express installationPlease note that the additional material referenced in the text is not available from IBM.

An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.