CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

expansion of peripheral CXCR5+CD8+ T cells, T follicular helper- like cells and CCR6+CD4+ T cells was observed in the participants with low viral load, potentially contributing to HIV-specific T cell responses. Conclusion: Low dose budigalimab was well-tolerated in Phase 1b studies in PLWH. The exploratory efficacy and biomarker responses highlighted encouraging characteristics of budigalimab in facilitating immune- mediated viral control, warranting further evaluation in Phase 2 studies. Live Single-Cycle SARS-CoV-2 Vaccine Elicits High Protection and Sterilizing Immunity Fabian Otte 1 , David Hauser 1 , Martin J. Lett 2 , Jacob Schoen 3 , Enja T. Kipfer 1 , Donata Hoffmann 3 , Nico J. Halwe 3 , Angele Breithaupt 3 , Lorenz Ulrich 3 , Tobias Britzke 3 , Lorena Urda 1 , Christian Mittelholzer 1 , Martin Beer 3 , Thomas Klimkait 1 1 University of Basel, Basel, Switzerland, 2 University of Oxford, Oxford, United Kingdom, 3 Friedrich Loeffler Institute, Isle of Riems, Germany Background: The SARS-CoV-2 pandemic called attention to an urgent need for fast and versatile vaccine development platforms to combat infectious RNA viruses. However, there is a continuous need for new, innovative tools to study viruses with large RNA genomes that have a pathogenic potential for human disease. Methods: We developed the novel vaccine concept of 'single-cycle infection viruses' (SCV) and completed the proof-of-concept for SARS-CoV-2 in the Syrian hamster model. 'CLEVER' (Cloning-free and Exchangeable system for Virus Engineering and Rescue), a DNA-based strategy for rapidly generating RNA viruses directly from PCR products, enabled the specific deletion of individual viral genes in a single step. We generated and profiled replication-deficient SARS-CoV-2 variants, for which the missing function could efficiently be complemented in trans. Animals were intranasally prime/boost vaccinated, challenged with wild-type SARS-CoV-2, and assessed for protection against viral infection, transmission, and pathogenesis. Moreover, primary human T cells were utilized to assess the potency in eliciting a specific T-cell response by our SCV candidate. Results: Several SCV candidates were produced and tested for functionality, stability, and safety (single-cycle properties) in vitro. After intranasal vaccination, animals tolerated the vaccine very well and experienced no weight loss, even when high doses were applied, validating excellent in vivo safety. All animals were fully protected against an autologous challenge with a high dose of infectious SARS-CoV-2 virus. With the specific deletion of three immune modulatory viral genes sterilizing immunity was achieved, preventing any viral spread to unvaccinated contact animals. Superior immune function was further shown by specific memory T cell responses in primary PBMCs from SARS-CoV-2 pre-exposed individuals. The SC vaccine effectively prevented viral infection with reduced inflammatory cytokine levels and pathology in the lung. In a direct comparison with the most recent bivalent mRNA vaccine superior immunity was confirmed for omicron-adapted SCV: full protection of vaccinated animals, no sign of viral replication and pathology in the contact animals, achieving again sterilizing immunity (Fig. 1). Conclusion: SCVs can induce broad protection and even sterilizing immunity against viruses, as demonstrated for SARS-CoV-2. We will use the concept to build a vaccine platform targeting other RNA viruses of concern, like Dengue or Chikungunya.

107

Oral Abstracts

108

Mini-Lecture on Neuropathogenesis of HIV Sharon R Lewin Doherty Institute for Infection and Immunity, Melbourne, Australia

Background: The central nervous system (CNS) presents a unique challenge for HIV cure strategies given the diverse infected cells that persist on antiretroviral therapy (ART) – including infected microglia, astrocytes and circulating T-cells, as well as the presence of the blood brain barrier (BBB), and the adverse acute and chronic consequences of localised inflammation. Numerous studies have now clearly demonstrated the persistence of intact and transcriptionally active cells in the CNS and that the frequency of infected cells and or free virus in the cerebrospinal fluid is associated with adverse neurological outcomes in people with HIV on ART. Using in vitro infection models, latency reversing agents (LRAs) have been shown to have greater potency in astrocytes compared to monocyte derived macrophages. Several clinical trials of LRAs that can cross the BBB, have demonstrated no adverse effects on the CNS in vivo, although the combination of disulfiram with vorinostat had significant neurotoxicity. Newer HIV-specific LRAs using Tat mRNA in a lipid nanoparticles will need to be evaluated in animal models to determine if the theoretical risk of neurotoxicity will be a barrier to further development. With the high interest in immunotherapy and gene therapy currently for an HIV cure, more data is needed to fully understand whether the specific intervention can cross the BBB, whether the intervention is effective in the CNS and whether there are CNS-specific adverse events of concern. Finally, in small prospective studies, antiretroviral therapy interruption has been shown to have limited adverse outcomes on the CNS, but some participants are at higher risk for an adverse outcome and these issue should be considered in the inclusion criteria of future HIV cure clinical trials. Our understanding of the impact of cure interventions on the CNS is critically important but currently limited and needs to be prioritised. Assessing the Contribution of Glial Activation to Cognitive Control and Declarative Memory in PWH Leah H Rubin 1 , Pauline Maki 2 , Yong Du 1 , Shannon Eileen Sweeney 1 , Riley O'Toole 1 , Raha M. Dastgheyb 1 , Eran F. Shorer 1 , Asante Kamkwalala 1 , Hannah Lee 1 , Joan Severson 3 , Il Minn 1 , Katrina A. Wugalter 2 , Arnold Bakker 1 , Martin Pomper 1 , Jennifer M. Coughlin 1 1 The Johns Hopkins University, Baltimore, MD, USA, 2 University of Illinois at Chicago, Chicago, IL, USA, 3 Digital Artefacts LLC, Iowa City, IA, USA Background: Virally suppressed people with HIV (VS-PWH) demonstrate impaired cognitive control (CC; executive function) and declarative memory (learning and memory), subdomains of the NIMH Research Domain Criteria framework. Building on evidence supporting a microglial contribution to central nervous system complications in VS-PWH, we used [11C]DPA-713 with positron emission tomography (DPA-PET) to track the translocator protein (TSPO) on activated microglia in the brains of VS-PWH. We hypothesized that VS-PWH (vs. controls) would show higher TSPO in brain regions that subserve CC (lateral prefrontal cortex [lPFC], dorsal anterior cingulate [dACC], inferior parietal lobe [IPL]) and declarative memory (PFC, hippocampus) and that higher TSPO in these regions of interest (ROI) would relate to poorer CC and declarative memory self-report and behavioral measures. Methods: Twenty-five VS-PWH and 18 demographically-similar control participants completed one 90-min DPA-PET scan with arterial blood sampling, structural brain magnetic resonance imaging, as well as CC (see Figure) and declarative memory measures (Buschke Selective Reminding test, Pattern Separation and Completion, Cognitive Failures Questionnaire-forgetfulness subscale). Regional [11C]DPA-713 total distribution volume (VT) values were

109

19

CROI 2024