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Safety and immunogenicity of investigational tuberculosis vaccine M72/AS01E-4 in people living with HIV in South Africa: an observer-blinded, randomised, controlled, phase 2 trial.
No full textBACKGROUND: M72/AS01E-4 is a recombinant fusion protein vaccine candidate derived from two Mycobacterium tuberculosis antigens (Mtb32A and Mtb39A) and AS01E-4 adjuvant. We evaluated safety and immunogenicity of M72/AS01E-4 in people living with HIV in South Africa. METHODS: In this observer-blinded, randomised, controlled, phase 2 trial, participants aged 16-35 years with well controlled HIV were enrolled from urban, semi-urban, and semi-rural settings in South Africa, including sites with high tuberculosis and HIV prevalence, as well as agricultural and mining communities. Participants were randomly assigned (1:1), stratified by site and interferon-gamma release assay (IGRA) status, to receive two intramuscular doses of M72/AS01E-4 or placebo. Eligibility criteria included antiretroviral therapy for at least 3 months, HIV viral load of less than 200 copies per mL, CD4 counts of 200 cells per μL or higher, and previous completion of tuberculosis preventive therapy and no tuberculosis history. The sponsor and its delegates, the laboratory team, investigators, site staff, and participants were blinded to randomisation, whereas an unblinded pharmacist who was not involved in trial procedures prepared placebo and reconstituted M72/AS01E-4 in unit-dose syringes covered with a blinding label. All participants who received at least one dose of either M72/AS01E-4 or placebo were included in the safety population for safety analyses. Immunogenicity analyses were conducted using the per-protocol population, which included participants who received the intervention as planned and did not substantially deviate from the protocol procedures. Safety assessments included solicited adverse events in the first 7 days after each dose, unsolicited adverse events in the first 28 days after each dose, and serious adverse events. Humoral responses were measured with ELISA and cellular responses were assessed using multiparameter flow cytometry, in the per-protocol population. This study is complete and is registered with ClinicalTrials.gov, NCT04556981. FINDINGS: Between Nov 17, 2020, and Aug 12, 2022, 402 eligible participants were assigned treatment, of whom 401 participants received at least one dose of M72/AS01E-4 (n=201; 175 [87%] were female and 26 [13%] were male; 196 [98%] were Black) or placebo (n=200; [176 [88%] were female and 24 [12%] were male; 196 [98%] were Black) and followed for a median duration of 372 days (IQR 364-389). Among M72/AS01E-4 recipients, solicited adverse events were more frequent, ranging from 17% (33 of 199) for gastrointestinal symptoms to 77% (140 of 183) for injection-site pain. Most events were mild to moderate, with severe events ranging from 0% (0 of 197) for swelling and (0 of 198) redness to 13% (24 of 183) for injection-site pain, resolving within 3 days. Unsolicited adverse events related to vaccine were mainly injection-site reactions in the M72/AS01E-4 group (8% [15 of 201] vs 1% [two of 200] in the placebo group), including erythema, pruritis, swelling, bruising, induration, and pain. No vaccine-related serious adverse events were reported. Among M72/AS01E-4 recipients at day 57 (1 month after dose two), M72-specific antibody geometric mean concentration (GMC) was 479·70 EU/mL (95% CI 421·79-545·56) with median magnitude of CD4 cells of 0·383% (IQR 0·177%-0·663). Among M72/AS01E-4 recipients, at day 57 GMCs were 559·49 EU/mL (95% CI 461·75-677·93) in with baseline IGRA positivity and 424·95 EU/mL (357·74-504·80) in those without; median magnitudes of CD4 cells were 0·447% (IQR 0·287-0·819) and 0·321% (0·147-0·581). INTERPRETATION: The two-dose regimen of the M72/AS01E-4 tuberculosis vaccine was immunogenic, with an acceptable safety profile. These outcomes led to the inclusion of people living with HIV in the ongoing global registration phase 3 trial. FUNDING: Gates Foundation and the Wellcome Trust
Improved resolution of influenza vaccination responses with high-throughput live virus microneutralisation.
No full textBACKGROUND: Influenza remains a significant threat to human and animal health. Assessing serological protection against influenza has relied upon haemagglutinin inhibition (HAI) assays, which are used to gauge existing immune landscapes, seasonal vaccine decisions and in systems vaccinology studies. HAI assays were first described in the 1940s. Here, we adapt our high-throughput live virus microneutralisation (LV-N) assay for SARS-CoV-2, benchmark against HAI assays, and report serological vaccine responsiveness in a cohort of older (> 65 yo) community dwelling adults. METHODS: Influenza-specific antibody responses were assessed in 73 individuals, before and after receipt of the adjuvanted 2021-22 Northern Hemisphere quadrivalent vaccine. We performed both HAI and LV-N assays against all four viruses represented in the vaccine [A/Cambodia/e0826360/2020 (H3N2), IVR-215 (A/Victoria/2570/2019-like) (H1N1)pdm09, B/Phuket/3073/2013 (B/Yamagata lineage), B/Washington/02/2019 (B/Victoria lineage)], using sera drawn before vaccination [range: d-82 to d-5], and days 7 [d6-10] and 181 [d156-200] after vaccination. We compared serological responses within each assay and between assays. RESULTS: Both the traditional HAI assay and our high-throughput live virus microneutralisation identified vaccine-induced boosts in antibody titres. We found population-level concordance between the two assays (Spearman's correlation coefficient range 0.49-0.88; all p ≤ 1.4 × 10-5). The improved granularity of microneutralisation was better able to estimate fold changes of responses and quantify the inhibitory effect of pre-existing antibody. CONCLUSIONS: Our high-throughput method offers an alternative approach to assess influenza-specific serological responses with improved resolution, with the potential to improve the annual assessment of existing antibody landscapes, to improve new vaccine strain evaluation, and to offer a step-change in systems vaccinology, and a facet of laboratory-based pandemic preparedness
SPIRIT 2025 checklist for EVOLVE study
No full textThis is a checklist submitted as a requirement of submission of EVOLVE-HBV protocol for publication at the Sage Journals. EVOLVE-HBV is an interdisciplinary study based at the Africa Health Research Institute (AHRI) aimed at quantifying and characterising HBV infection in the KwaZulu-Natal (KZN) province, South Africa. The study aims to develop insights into HBV by assessing population knowledge, epidemiology, clinical features and laboratory characteristics to enhance local care pathways.</p
Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells.
No full textSeveral mechanisms of resistance of cancer cells to cyclin-dependent kinase inhibitors (CDKi) have been identified, including the upregulation of metabolic regulators such as glutaminase. However, whether such resistance mechanisms represent optimal targets has not been determined. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDKi selectively targeting CDK4/6, or Telaglenastat, a selective glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenastat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenastat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenastat. In conclusion, combination with Telaglenastat optimally forestalls acquired resistance to Palbociclib in cancer cells
From research to action: recommendations for Charles Bonnet syndrome care and policy.
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Knowledge, attitudes and practices to hepatitis B among South African primary healthcare staff
No full textBackground: Hepatitis B virus (HBV), a significant cause of liver disease globally, is recognised as a 2030 elimination target by the World Health Organization (WHO). Healthcare workers (HCWs) require appropriate HBV knowledge to identify, manage and prevent HBV.
Aim: We investigated the knowledge, attitude and practices (KAP) pertaining to HBV among HCWs to establish insights into awareness and inform the delivery of training.
Setting: The study was conducted among HCWs of 18 primary healthcare facilities in Bloemfontein, Free State province, South Africa.
Methods: Data were collected via anonymous, self-applied, 28-question-questionnaires in English. Data were captured on a Microsoft Excel spreadsheet and analysed by a biostatistician, using Statistical Analyses Software (SAS 9.4).
Results: The response rate was 88% (88/100), and median participant age was 44 years. Participants were mostly female (83%), professional nurses (65%) with more than 8 years of experience (60%). Median scores were 83% for epidemiology and transmission, 50% for clinical picture, 44% for laboratory diagnosis, 40% for management and 40% for prevention. No difference was noted based on number of years of experience.
Conclusion: Considerable gaps in KAP to HBV were noted among primary HCWs in Bloemfontein. Larger studies are needed to ascertain the KAP towards HBV among South African HCWs, to identify areas for enhanced training.
Contribution: Hepatitis B virus, an important cause of liver disease in Africa, is poorly identified and managed. Our study highlights the need to strengthen HCW education to ensure individuals are appropriately diagnosed, managed and educated on preventative measures, to reduce the burden of disease
Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants.
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The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound.
No full textOf 250 Plasmodium species, 6 infect humans, with P. falciparum causing over 95% of 600,000 annual malaria-related deaths. Its pathology arises from host cell remodelling driven by over 400 exported parasite proteins, including the FIKK kinase family. About one million years ago, a bird-infecting Plasmodium species crossed into great apes and a single non-exported FIKK kinase gained an export element. This led to a rapid expansion into 15-21 atypical, exported Ser/Thr effector kinases. Here, using genomic and proteomic analyses, we demonstrate FIKK differentiation via changes in subcellular localization, expression timing and substrate motifs, which supports an individual important role in host-pathogen interactions. Structural data and AlphaFold2 predictions reveal fast-evolving loops in the kinase domain that probably enabled rapid functional diversification for substrate preferences. One FIKK evolved exclusive tyrosine phosphorylation, previously thought absent in Plasmodium. Despite divergence of substrate preferences, the atypical ATP binding pocket is conserved and we identified a single compound that inhibits all FIKKs. A pan-specific inhibitor could reduce resistance development and improve malaria control strategies
MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition.
No full textHuman N-myristoyltransferases (NMTs) catalyze N-terminal protein N-myristoylation and are promising targets in cancer, with an emerging mechanistic rationale for targeted therapy. Here, we screened 245 cancer cell lines against IMP-1320, a potent NMT inhibitor (NMTi), and conducted pathway-level analyses to identify that deregulated MYC increases cancer cell sensitivity to NMTis. Proteomics on detergent-enriched membrane fractions in MYC or MYCN-deregulated cancer cell models revealed that cell death is associated at least in part with loss of membrane association of mitochondrial respiratory complex I. This is concurrent with loss of myristoylation and degradation of the complex I assembly factor NDUFAF4, and induction of mitochondrial dysfunction, driven by MYC or MYCN-deregulation. NMTis eliminated or suppressed MYC- and MYCN-driven tumors in vivo without overt toxicity, suggesting that this constitutive co-translational protein modification can be targeted in MYC-driven cancers
Early coordination of cell migration and cardiac fate determination during mammalian gastrulation.
No full textDuring gastrulation, mesodermal cells derived from distinct regions are destined to acquire specific cardiac fates after undergoing complex migratory movements. Here, we used light-sheet imaging of live mouse embryos between gastrulation and heart tube formation to track mesodermal cells and to reconstruct lineage trees and 3D migration paths for up to five cell divisions. We found independent progenitors emerging at specific times, contributing exclusively to left ventricle/atrioventricular canal (LV/AVC) or atrial myocytes. LV/AVC progenitors differentiated early to form the cardiac crescent, while atrial progenitors later generated the heart tube's Nr2f2+ inflow tract during morphogenesis. We also identified short-lived multipotent progenitors with broad potential, illustrating early developmental plasticity. Descendants of multipotent progenitors displayed greater dispersion and more diverse migratory trajectories within the anterior mesoderm than the progeny of uni-fated progenitors. Progenitors contributing to extraembryonic mesoderm (ExEm) exhibited the fastest and most dispersed migrations. In contrast, those giving rise to endocardial, LV/AVC, and pericardial cells showed a more gradual divergence, with late-stage behavioural shifts: endocardial cells increased in speed, while pericardial cells slowed down in comparison to LV/AVC cells. Together, these data reveal patterns of individual cell directionality and cardiac fate allocation within the seemingly unorganised migratory pattern of mesoderm cells