Biology subjects

Aid, M.

Publications and source records attributed to Aid, M..

11 recordsLinked to original sources

bioRxiv2026

Early innate immune signatures correlate with Ad26.COV2.S vaccine durability and protective efficacy

The innate immune system is rapidly activated following antigen exposure and plays a critical role in shaping the ensuing adaptive immune responses. In this study, we performed bulk RNA sequencing and proteomic profiling in a cohort of 25 rhesus macaques following Ad26.COV2.S immunization to characterize early innate correlates of vaccine immunogenicity and protection. Our results show that innate immune activation occurred as early as day 1 post-vaccination and demonstrated an systemic enrichment of antiviral interferon pathways, interleukin signaling, and innate immune cell signatures. These early transcriptomic signatures correlated positively with humoral and cellular immune responses at 6 weeks following vaccination and correlated inversely with viral loads following SARS-CoV-2 challenge. Similar correlates of immunogenicity were observed in a cohort of 25 adult healthy participants vaccinated with Ad26.COV2.S. Taken together, these findings highlight the importance of early activation of the innate immune system for Ad26.COV2.S vaccine immunogenicity and protective efficacy. Graphical SummaryGraphical summary of the model proposed by our findings. Day 1 innate immune signatures are protective of long-term protection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/731069v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@308acaorg.highwire.dtl.DTLVardef@e7e969org.highwire.dtl.DTLVardef@18d1a18org.highwire.dtl.DTLVardef@ac4fb0_HPS_FORMAT_FIGEXP M_FIG C_FIG IMPORTANCEEarly vaccine induction of innate immunity may be critical for vaccine immunogenicity and protective efficacy. In this study, we evaluated innate immune responses following Ad26.COV2.S vaccination in both rhesus macaques and humans. Early induction of innate immune signatures on day 1 following vaccination correlated with subsequent development of adaptive immune responses. These data suggest that the immune programming that occurs immediately after vaccination dictates immunogenicity weeks or months later.

microbiology↗

bioRxiv2025

Origin and Correlates of Viral Rebound in SIV-Infected Rhesus Macaques Following ART Discontinuation

The vast majority of persons living with HIV-1 who discontinue antiretroviral therapy (ART) demonstrate viral rebound, but the tissue-level events that lead to rebound viremia are poorly understood. Here we report the origin, dynamics, and correlates of viral rebound in 16 rhesus macaques (RMs) infected with molecularly barcoded SIVmac239M, treated with ART for 70 weeks, and necropsied on day 12 after ART discontinuation. Barcode analysis of plasma following ART discontinuation identified 1 to 38 rebounding barcode-defined viral lineages per animal, with 1 to 4 rebounding lineages contributing to first measurable rebound viremia. Analysis of barcode viral RNA (vRNA) expression in necropsy tissues revealed presumptive anatomic origin sites for 56 of 175 total rebounding viral lineages, with significant enrichment in the gastrointestinal (GI) tract and GI-associated lymph nodes. Daily transcriptomic and proteomic profiling in peripheral blood following ART discontinuation showed upregulation of pathways related to T cell signaling, cytokine responses, and cellular metabolism prior to detectable rebound viremia. These data suggest that viral rebound following ART discontinuation is initiated by local tissue replication of a limited number of clonal lineages, followed by systemic expansion of the initial rebounding lineages and serial initiation of replication of multiple additional clonal lineages. These findings provide mechanistic insights into the processes that result in viral rebound following ART discontinuation and will contribute to next generation HIV-1 cure strategies.

microbiology↗

bioRxiv2025

Longitudinal transcriptomic analysis of SIV-infected rhesus macaques reveals peripheral immune dynamics throughout untreated SIV infection and long-term antiretroviral therapy

Developing a working knowledge of immune dynamics during prolonged infection and treatment has become critical for both advancing HIV cure strategies and understanding non-AIDS comorbidities, given rises in the age and average time spent on antiretroviral therapy (ART) among people living with HIV. However, at present, we do not fully appreciate the ways in which prolonged suppressive therapy influences immune function. Toward addressing this key knowledge gap comprehensively, we applied single-cell RNA-sequencing (scRNA-seq) to longitudinally profile peripheral blood mononuclear cells from SIV-infected non-human primates longitudinally. Our data reveal significant immune shifts during acute and chronic infection, as well as over five years of subsequent ART. We observe a decline in CD4+ T cells and an increase in aberrant B cells and CD16+ monocytes during untreated chronic infection, as well as widespread dampened transcriptional activity. Further, we uncover transcriptional signatures suggestive of unresolved immune dysregulation during long-term suppressive therapy - most prominently among myeloid cell populations. By examining concurrent measurements of intact proviral DNA, we link peripheral responses to reservoir size via IPDA. We furthermore identify ribosomal-associated pathways as key differentiators of infection stage, treatment status, and time on ART. Finally, we tested whether previously published transcriptional correlates of differential outcomes (e.g. viral rebound, vaccine efficacy) changed over time on ART. Overall, our findings capture dynamic immune remodeling from acute infection through long-term ART, highlighting complexities in achieving complete immune recovery that may influence future therapeutic strategies.

immunology↗

bioRxiv2025

Dosing and Serostatus Shape the Efficacy of Adenovirus, mRNA, and Protein Vaccines

Despite the widespread use of adenovirus, mRNA, and protein-based vaccines during the COVID-19 pandemic, their relative immunological profiles and protective efficacies remain incompletely defined. Here, we compared antigen kinetics, innate and adaptive immune responses, and protective efficacy following Ad5, mRNA, and protein vaccination in mice. Ad5 induced the most sustained antigen expression, but mRNA induced the most potent interferon responses, associated with robust antigen presentation and costimulation. Unlike Ad5 vaccines, which were hindered by pre-existing vector immunity, mRNA vaccines retained efficacy after repeated use. As a single-dose regimen, Ad5 vaccines elicited superior immune responses. However, as a prime-boost regimen, and particularly in Ad5 seropositive mice, mRNA vaccines outperformed the other vaccine platforms. These findings highlight strengths of each vaccine platform and underscore the importance of host serostatus in determining optimal vaccine performance.

immunology↗

bioRxiv2024

Early spatiotemporal evolution of the immune response elicited by adenovirus serotype 26 vector vaccination in mice

As the first responder to immunological challenges, the innate immune system shapes and regulates the ensuing adaptive immune response. Many clinical studies evaluating the role of innate immunity in initiating vaccine-elicited adaptive immune responses have largely been confined to blood due to inherent difficulty in acquiring tissue samples. However, the absence of vaccine-site and draining lymph node information limits understanding of early events induced by vaccination that could potentially shape vaccine-elicited immunity. We therefore utilized a mouse model to investigate the spatiotemporal evolution of the immune response within the first 24 hours following intramuscular adenovirus serotype 26 (Ad26) vector vaccination in tissues. We show that the Ad26 vaccine-elicited innate immune response commences by one hour and rapidly evolves in tissues and blood within the first 24 hours as reflected by the detection of cytokines, chemokines, cellular responses, and transcriptomic pathways. Furthermore, serum levels of IL-6, MIG, MIP-1, and MIP-1{beta} at 6 hours post-vaccination correlated with the frequency of vaccine-elicited memory CD8+ T cell responses evaluated at 60 days post-vaccination in blood and tissues. Taken together, our data suggests that the immune response to Ad26 vector vaccination commences quickly in tissues by one hour and that events by as early as 6 hours post-vaccination can shape vaccine-elicited CD8+ T cell responses at later memory time points. IMPORTANCEPrior studies have largely concentrated on innate immune activation in peripheral blood following vaccination. In this study, we report the detailed spatial and temporal innate immune activation in tissues following Ad26 vaccination in mice. We observed rapid innate activation rapidly not only in peripheral blood but also in draining lymph nodes and at the site of inoculation. Our findings provide a more detailed picture of host response to vaccination than previously reported.

immunology↗

bioRxiv2024

Protective threshold of a potent neutralizing Zika virus monoclonal antibody in rhesus macaques

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused a global pandemic in 2016-2017 with continued ongoing transmission at low levels in several countries. In the absence of an approved ZIKV vaccine, neutralizing monoclonal antibodies (mAbs) provide an option for the prevention and treatment of ZIKV infection. Previous studies identified a potent neutralizing human mAb ZIKV-117 that reduced fetal infection and death in mice following ZIKV challenge. In this study, we report exquisite potency of ZIKV-117 in a titration study in rhesus macaques to protect against ZIKV challenge. We show complete protection at a dose of 0.016 mg/kg ZIKV-117, which resulted in median serum concentrations of 0.13 {micro}g/mL. The high potency of this mAb supports its potential clinical development as a novel biotherapeutic intervention for ZIKV. ImportanceIn this study, we report the potency of the ZIKV-specific neutralizing antibody ZIKV-117 against ZIKV challenge in a titration study rhesus macaques. This high potency supports the further development of this mAb for ZIKV.

microbiology↗

bioRxiv2024

Persistent Activation of Chronic Inflammatory Pathways in Long Covid

Long Covid, or Post-Acute Sequelae of COVID-19 (PASC), involves a spectrum of chronic symptoms following resolution of acute SARS-CoV-2 infection. Current hypotheses for the pathogenesis of Long Covid include persistent SARS-CoV-2, activation of other viruses, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction, and complement activation. We evaluated 142 participants, including uninfected controls (N=35), acutely infected individuals (N=54), convalescent controls (N=25), and Long Covid patients (N=28), by comprehensive immunologic, virologic, transcriptomic, and proteomic analyses. Long Covid was characterized by persistent inflammatory pathways compared with convalescent controls and uninfected controls, including upregulation of IL-6 and JAK-STAT pathways as well as activation of coagulation, complement, metabolism, and T cell exhaustion pathways. Moreover, robust activation of these pathways during acute COVID-19 infection correlated with the subsequent development of Long Covid. In an independent validation cohort (N=47), Long Covid patients had higher levels of plasma IL-6R compared with convalescent controls and uninfected controls. These data demonstrate that Long Covid is characterized by persistent activation of chronic inflammatory pathways, suggesting novel therapeutic targets and biomarkers of disease.

immunology↗

bioRxiv2023

Attenuated Mycobacterium tuberculosis Vaccine Protection in a Low Dose Murine Challenge Model

Bacillus Calmette-Guerin (BCG) remains the only clinically approved tuberculosis (TB) vaccine despite limited efficacy. Preclinical studies of next generation TB vaccines have typically used a murine aerosol challenge model that employs a high supraphysiologic challenge dose. Here we show that the protective efficacy of a live attenuated Mycobacterium tuberculosis (Mtb) vaccine candidate {Delta}LprG markedly exceeds that of BCG in a low dose murine aerosol challenge model. BCG vaccination reduced bacterial loads but failed to prevent establishment or dissemination of infection in this model. In contrast, {Delta}LprG prevented detectable infection in 61% of mice and resulted in striking anatomic containment of 100% breakthrough infections to a single lung. Protection was partially abrogated in a repeated low dose challenge model, which revealed serum IL-17A, IL-6, CXCL2, CCL2, IFN-{gamma}, and CXCL1 as correlates of protection. These data demonstrate that {Delta}LprG provides strikingly increased protection compared to BCG, including reduced detectable infection and anatomic containment, in a low dose murine challenge model.

microbiology↗

bioRxiv2022

Rapid Loss of CD4 T Cells by Pyroptosis During Acute SIV Infection in Rhesus Macaques

The mechanisms underlying depletion of CD4 T cells during acute HIV-1 infection are not well understood. Here we show that caspase-1-induced pyroptosis, a highly inflammatory programmed cell death pathway, is the dominant mechanism responsible for the rapid depletion of CD4 T cells in gut-associated lymphatic tissue (GALT), spleen, and lymph nodes during acute simian immunodeficiency virus (SIV) infection in rhesus macaques. Upregulation of interferon-gamma inducible factor 16 (IFI16), a host DNA sensor that triggers pyroptosis, was also observed in tissue-resident CD4 T cells and correlated with viral loads and CD4 T cell loss. In contrast, caspase-3-mediated apoptosis and viral cytotoxicity only accounted for a small fraction of CD4 T cell death. Other programmed cell death mechanisms, including mitochondria-induced caspase-independent cell death, necroptosis, and autophagy, did not significantly contribute to CD4 T cell depletion. These data support a model in which caspase-1-mediated pyroptosis is the principal mechanism that results in CD4 T cell loss in the GALT and lymphoid organs and release of proinflammatory cytokines. These findings contribute to our understanding of the pathogenesis of acute SIV infection and have important implications for the development of therapeutic strategies. ImportanceDifferent mechanisms for CD4 T cell depletion during acute HIV-1 infection have been proposed. In this study, we should in SIV infected rhesus macaques that depletion of CD4 T cells is primarily due to pyroptosis. Other pathophysiologic mechanisms may also contribute in a minor way to CD4 T cell depletion.

microbiology↗

bioRxiv2021

Ad26.COV2.S Prevents SARS-CoV-2 Induced Pathways of Inflammation and Thrombosis in Hamsters

Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease, and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 challenge in hamsters stimulates antiviral, myeloid, and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, single dose immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways such that the gene expression profiles of vaccinated hamsters are comparable to uninfected animals. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses. These data provide further insights into the mechanisms of Ad26.COV2.S based protection against severe COVID-19 in hamsters. Author SummaryIn this study, we show that vaccination with Ad26.COV2.S protected SARS-CoV-2 challenged hamsters from developing severe COVID-19 disease by attenuating excessive proinflammatory responses, such as IL-6 and IL-1, macrophages and neutrophils signaling. Ad26 vaccination also prevented the upregulation of pathways associated with thrombosis such coagulation and clotting cascades associated with infection, and the transcriptomic profiles of vaccinated animals were largely comparable to control uninfected hamsters. In contrast, SARS-CoV-2 challenged unvaccinated hamsters showed significant increase of these proinflammatory and prothrombotic pathways and significant weight loss compared to vaccinated hamsters.

microbiology↗

bioRxiv2021

IL-10 driven memory T cell survival and Tfh differentiation promote HIV persistence

Mechanisms regulating HIV persistence are complex and not well understood. Increased IL-10 levels were positively associated with HIV reservoir in blood and lymph nodes (LN) of treated HIV aviremic individuals. In LNs, B cells, regulatory T cells, follicular T helper cells (Tfh), monocytes and macrophages contributed to the frequencies of IL10+ cells. Cells with HIV DNA in LNs were in close proximity to IL-10+ cells and/or had the active form of STAT3, the transcription downstream of IL-10. Gene signatures and proteins associated to cell survival, Co-inhibitory receptors expression, maintenance of memory T cells, immune metabolism and Tfh frequencies were all modulated by IL-10 and associated with HIV reservoir persistence. In vitro, STAT3 knockout or neutralization of IL-10, reverted all the aforementioned pathways and resulted in 10-fold decay in HIV reservoir. Collectively, these results provide strong evidence for a pivotal role of IL-10 in HIV persistence, and a potential therapeutic strategy for HIV cure.

immunology↗