Meeting report: South African Medical Research Council Standard of Care in Clinical Research in Low- And Middle-Income Settings Summit, November 2017

A cornerstone of HIV prevention clinical trials is providing a combination prevention package to all trial participants. The elements included in that standard of care (SoC) package evolve as new prevention modalities are developed. Pre-exposure prophylaxis (PrEP) was recommended by the World Health Organization for persons at high risk of acquiring HIV, but not all countries immediately adopted those recommendations. The South African Medical Research Council (SAMRC) convened a summit to discuss issues relating to SoC and PrEP in HIV prevention clinical trials taking place in lower- to middle-income countries (LMIC). Policymakers, regulators, ethicists, experts in law, researchers, representatives of advocacy groups, and the HIV Vaccine Trials Network (HVTN) presented a framework within which SoC principles could be articulated. A group of subject matter experts presented on the regulatory, ethical, scientific, and historic framework of SoC in clinical trials, focusing on PrEP in South Africa. Summit participants discussed how and when to include new HIV treatment and prevention practices into existing clinical guidelines and trial protocols, as well as the opportunities for and challenges to scaling up interventions. The summit addressed challenges to PrEP provision, such as inconsistent efficacy amongst different populations and various biological, virological, and immunological explanations for this heterogeneity. Advocates and community members propagated the urgent need for accessible interventions that could avert HIV infection. The meeting recommended supporting access to PrEP in HIV prevention trials by (1) developing PrEP access plans for HIV vaccine trials, (2) creating a PrEP fund that would supply PrEP to sites conducting HIV prevention trials via a central procurement mechanism, and (3) supporting the safety monitoring of PrEP. This report summarizes the presentations and discussions from the summit in order to highlight the importance of SoC in HIV prevention clinical trials

High asymptomatic carriage with the Omicron variant in South Africa

We report a 23% asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) Omicron carriage rate in participants being enrolled into a clinical trial in South Africa, 15-fold higher than in trials before Omicron. We also found lower CD4 + T-cell counts in persons with human immunodeficiency virus (HIV) strongly correlated with increased odds of being SARS-CoV-2 polymerase chain reaction (PCR) positive.The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) grants. The Sisonke study was funded by the National Treasury of South Africa; the National Department of Health; Solidarity Response Fund NPC; The Michael & Susan Dell Foundation; The Elma Vaccines and Immunization Foundation; and the Bill & Melinda Gates Foundation.https://academic.oup.com/cidam2023Paediatrics and Child Healt

Safety, tolerability, pharmacokinetics, and immunological activity ...

This phase 1 study showed the feasibility of combining anti-HIV bnAbs targeting different sites on the HIV envelope in people living without HIV. It also showed that the dual-antibody and triple-antibody combinations were as effective as the individual antibodies at neutralisation, thus justifying a combination approach going forward for additional monoclonal antibody studies for HIV prevention. The fact that modelling predicted the combination neutralisation titre on the basis of the single antibody titres will be valuable for future trial design of different antibody combinations

Evaluation of cell-based and surrogate SARS-CoV-2 neutralization assays

Determinants of protective immunity against SARS-CoV-2 infection require the development of well-standardized, reproducible antibody assays. This need has led to the emergence of a variety of neutralization assays. Head-to-head evaluation of different SARS-CoV-2 neutralization platforms could facilitate comparisons across studies and laboratories. Five neutralization assays were compared using forty plasma samples from convalescent individuals with mild-to-moderate COVID-19: four cell-based systems using either live recombinant SARS-CoV-2 or pseudotyped viral particles created with lentivirus (LV) or vesicular stomatitis virus (VSV) packaging and one surrogate ELISA-based test that measures inhibition of the spike protein receptor binding domain (RBD) binding its receptor, human angiotensin converting enzyme 2 (hACE2). Vero, Vero E6, HEK293T expressing hACE2, and TZM-bl cells expressing hACE2 and transmembrane serine protease 2 were tested. All cell-based assays showed 50% neutralizing dilution (ND50) geometric mean titers (GMTs) that were highly correlated (Pearson r = 0.81–0.89) and ranged within 3.4-fold. The live-virus assay and LV-pseudovirus assays with HEK293T/hACE2 cells showed very similar mean titers: 141 and 178, respectively. ND50 titers positively correlated with plasma IgG targeting SARS-CoV-2 spike and RBD (r = 0.63–0.89), but moderately correlated with nucleoprotein IgG (r = 0.46–0.73). ND80 GMTs mirrored ND50 data and showed similar correlation between assays and with IgG concentrations. The VSV-pseudovirus assay and LV-pseudovirus assay with HEK293T/hACE2 cells in low and high-throughput versions were calibrated against the WHO SARS-CoV-2 IgG standard. High concordance between the outcomes of cell-based assays with live and pseudotyped virions enables valid cross-study comparison using these platforms. 24

Role of cholesterol in<i style=""> Mycobacterium tuberculosis </i>infection

407-411Mycobacterium tuberculosis (MTB) acquisition and utilization of nutrients within the host cell is poorly understood, although it has been hypothesized that host lipids probably play an important role in MTB survival. Cholesterol has recently been identified as an important lipid for mycobacterial infection. The mce4 transport system is required for cholesterol import into bacterial cells, and deletion of mce4 locus resulted in severe attenuation in a chronic mouse model of infection. However, it has remained unclear what additional bacterial functions were required for utilization of this sterol. We have found that the igr locus, which was previously found essential for intracellular growth and virulence of MTB, is required for cholesterol metabolism: igr-deficient bacteria cannot grow using cholesterol as a primary carbon source. The growth-inhibitory effect of cholesterol in vitro depends on cholesterol import, as the Δigr mutant growth defect during the early phase of disease is completely suppressed by mutating mce4, implicating cholesterol intoxication as the primary mechanism of attenuation. We conclude that M. tuberculosis metabolizes cholesterol throughout the course of infection, and that degradation of this sterol is crucial for bacterial persistence

igr Genes and Mycobacterium tuberculosis Cholesterol Metabolism▿ †

Recently, cholesterol was identified as a physiologically important nutrient for Mycobacterium tuberculosis survival in chronically infected mice. However, it remained unclear precisely when cholesterol is available to the bacterium and what additional bacterial functions are required for its metabolism. Here, we show that the igr locus, which we previously found to be essential for intracellular growth and virulence of M. tuberculosis, is required for cholesterol metabolism. While igr-deficient strains grow identically to the wild type in the presence of short- and long-chain fatty acids, the growth of these bacteria is completely inhibited in the presence of cholesterol. Interestingly, this mutant is still able to respire under cholesterol-dependent growth inhibition, suggesting that the bacteria can metabolize other carbon sources during cholesterol toxicity. Consistent with this hypothesis, we found that the growth-inhibitory effect of cholesterol in vitro depends on cholesterol import, as mutation of the mce4 sterol uptake system partially suppresses this effect. In addition, the Δigr mutant growth defect during the early phase of disease is completely suppressed by mutating mce4, implicating cholesterol intoxication as the primary mechanism of attenuation. We conclude that M. tuberculosis metabolizes cholesterol throughout infection

Developing tuberculosis vaccines for people with HIV: consensus statements from an international expert panel

New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV