A5005882398- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Chronic Lymphocytic Leukemia Research
- Cytomegalovirus and herpesvirus research
- vaccines and immunoinformatics approaches
- Glycosylation and Glycoproteins Research
- Herpesvirus Infections and Treatments
- Bacteriophages and microbial interactions
- Biochemical and Molecular Research
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- Viral-associated cancers and disorders
- Escherichia coli research studies
- Drug Transport and Resistance Mechanisms
- CAR-T cell therapy research
- Ginseng Biological Effects and Applications
- Toxin Mechanisms and Immunotoxins
- Viral gastroenteritis research and epidemiology
- Pneumocystis jirovecii pneumonia detection and treatment
- Animal Behavior and Welfare Studies
- Hematopoietic Stem Cell Transplantation
- Biosensors and Analytical Detection
Scripps Research Institute
2020-2025
International AIDS Vaccine Initiative
2020-2024
Ragon Institute of MGH, MIT and Harvard
2022-2024
Scripps Health
2020
Kaketsuken (Japan)
2015
University of Pennsylvania
2005
Goethe University Frankfurt
1997-2002
Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the vaccine-priming candidate eOD-GT8 60mer adjuvanted with AS01
Vaccines generate high-affinity antibodies by recruiting antigen-specific B cells to germinal centers (GCs), but the mechanisms governing recruitment GCs on secondary challenges remain unclear. Here, using preclinical SARS-CoV and HIV mouse models, we demonstrated that elicited during primary humoral responses shaped naive cell exposures. The from could either enhance or, conversely, restrict GC participation of cells: broad-binding, low-affinity, low-titer enhanced recruitment, whereas,...
An adjuvant composed of saponin and a TLR4 agonist acts by enhancing lymph flow antigen entry into nodes.
Abstract Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity several stabilized SOSIP constructs both free trimers and presented a nanoparticle. We applied cryoEM-based method for high-resolution mapping polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralization...
Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for vaccine design. Most bnAbs engage Env with an uncommonly long heavy-chain complementarity-determining 3 (HCDR3), suggesting that rarity of bnAb precursors poses a challenge priming. We created precursor sequence definitions HCDR3-dependent and searched related in human antibody ultradeep sequencing data from 14 HIV-unexposed donors. found potential majority donors only two long-HCDR3...
The induction of durable protective immune responses is the main goal prophylactic vaccines, and adjuvants play a role as drivers such responses. Despite advances in vaccine strategies, safe effective HIV remains significant challenge. use an appropriate adjuvant crucial to success vaccines. Here we assessed saponin/MPLA nanoparticle (SMNP) with envelope (Env) trimer, evaluating safety impact multiple variables including dose (16-fold range), immunization route, composition on establishment...
Significance Rational development of successful vaccines requires utilization predictive models vaccination. One approach for an HIV vaccine has been to study broadly neutralizing antibodies (bnAbs) and revert the mutations back germline. However, there are limitations such models. Therefore, we generated three knockin mice expressing B cell receptors (BCRs) from authentic naive VRC01-class cells healthy human donors (“HuGL” mice). This revealed that BCRs indeed competent antigen-specific...
One of the rate-limiting steps in analyzing immune responses to vaccines or infections is isolation and characterization monoclonal antibodies. Here, we present a hybrid structural bioinformatic approach directly assign heavy light chains, identify complementarity-determining regions, discover sequences from cryoEM density maps serum-derived polyclonal antibodies bound an antigen. When combined with next-generation sequencing repertoires, were able specifically clonal family members,...
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) the CD4-binding site of HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as soluble self-assembling nanoparticle mouse models. In model with three humanized B cell lineages bearing distinct VRC01-precursor receptors (BCRs) similar affinities for eOD-GT8, all could...
Immunodominance to nonneutralizing epitopes is a roadblock in designing vaccines against several diseases of high interest. One hypothetical possibility that limited CD4 T cell help B cells normal germinal center (GC) response results selective recruitment abundant, immunodominant cells. This central issue HIV envelope glycoprotein (Env) vaccine designs, because precursors broadly neutralizing are rare. Here, we sought elucidate whether modulating the quantity can influence and competition...
We have identified four small molecules that boost transduction of cells by human immunodeficiency virus (HIV) and investigated their mechanism action. These include etoposide camptothecin, which induce DNA damage inhibiting religation cleaved topoisomerase-DNA complexes, taxol, interferes with the function microtubules, aphidicolin, inhibits polymerases. All compounds arrest cell cycle at G2/M, though in addition high concentrations aphidicolin G1. find early events HIV replication,...
Resource1 December 2020Open Access Transparent process Multiplexed CRISPR/CAS9-mediated engineering of pre-clinical mouse models bearing native human B cell receptors Xuesong Wang The Ragon Institute Massachusetts General Hospital, Technology and Harvard University, Cambridge, MA, USAThese authors contributed equally to this work Search for more papers by author Rashmi Ray Sven Kratochvil USA Eleonora Melzi orcid.org/0000-0002-1520-735X Ying-Cing Lin Sophie Giguere Liling Xu John Warner...
Abstract Adjuvants and antigen delivery kinetics can profoundly influence B cell responses should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen change depending on the method. To promote extended immunogen bioavailability to present a multivalent form, native-HIV Env trimers are modified with short phosphoserine peptide linkers that tight binding aluminum hydroxide (pSer:alum)....
A protective vaccine against HIV will likely need to induce broadly neutralizing antibodies (bnAbs) that engage relatively conserved epitopes on the envelope glycoprotein (Env) trimer. Nearly all strategies bnAbs require use of complex immunization regimens involving a series different immunogens, most which are Env trimers. Producing protein-based clinical material evaluate such in humans presents major challenges cost and time. Furthermore, with trimers as soluble proteins induces strong...
Objective: To investigate the prevalence and magnitude of M184V-mediated changes in susceptibility to zalcitabine, didanosine, stavudine abacavir (1592U89 succinate) a cohort lamivudine-treated patients. Design methods: A total 255 samples from patients treated with lamivudine zidovudine or without other nucleoside reverse transcriptase inhibitors (NRTI) were analysed for zidovudine, lamivudine, didanosine using recombinant virus assay. Seventy-three originated exposed only. subset 27 was...
The induction of durable protective immune responses is the main goal prophylactic vaccines, and adjuvants play an important role as drivers such responses. Despite advances in vaccine strategies, a safe effective HIV remains significant challenge. use appropriate adjuvant crucial to success vaccines. Here we assessed saponin/MPLA nanoparticle (SMNP) with envelope (Env) trimer, evaluating safety impact multiple variables including dose (16-fold range), immunization route, composition on...
Abstract In the ongoing effort to develop a vaccine against HIV, approaches that promote strong germinal center (GC) responses may be critical enable selection and affinity maturation of rare B cell clones capable evolving produce broadly neutralizing antibodies. We previously demonstrated an approach for enhancing GC overall humoral immunity elicited by alum-adjuvanted protein immunization via use phosphoserine (pSer) peptide-tagged immunogens stably anchor alum particles ligand exchange...
ABSTRACT CD4 down-modulation is essential for the production of human immunodeficiency virus (HIV) infectious particles. Disease progression correlates with enhanced viral induced down-modulation, and a subset long-term nonprogressors carry viruses defective in this function. Despite multiple pieces evidence highlighting importance function pathogenesis vivo, to date, HIV-induced has not been used as target intervention. We describe here HIV-based vectors that deliver truncated molecules...
Viruses can evade the host immune system by displaying numerous glycans on their surface "spike-proteins" that cover epitopes. We have developed an ultrasensitive "single-pot" method to assess glycan occupancy and extent of processing from high-mannose complex forms at each N-glycosylation site. Though aimed characterizing glycosylation viral spike-proteins as potential vaccines, this is applicable for analysis site-specific any glycoprotein.
Abstract Broadly neutralizing antibodies (bnAbs) have promise to protect against HIV infection, but induction of bnAbs by immunization is an unsolved vaccine design challenge. Germline-targeting priming immunogens aim initiate the specifically activating rare bnAb-precursor B cells that can subsequently be matured using suitable heterologous boosting and shepherding immunogens. Several pre-clinical studies, IAVI G001 human clinical trial, demonstrated ability a germline-targeting immunogen,...
SUMMARY Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies non-human primates (NHPs) comparing the most common clinical adjuvant alum with Saponin/MPLA Nanoparticles (SMNP), novel ISCOMs-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific...
HIV-1 envelope (Env) proteins designed to induce neutralizing antibody responses allow study of the role affinities (equilibrium dissociation constant [KD]) and kinetic rates (association/dissociation rates) on B cell antigen recognition. It is unclear whether affinity discrimination during activation based solely Env protein binding KD cells discriminate among similar that bind with different rates. Here, we use a panel Ramos lines expressing immunoglobulin M (IgM) receptors (BCRs)...
Abstract Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies nonhuman primates (NHPs) comparing the most common clinical adjuvant aluminum hydroxide (alum) with saponin/monophosphoryl lipid A nanoparticles (SMNP), an immune-stimulating complex–like adjuvant. SMNP elicited substantially stronger humoral immune responses than...