Diverse priming outcomes under conditions of very rare precursor B cells DOI Creative Commons
Patrick Madden, Ester Marina-Zárate, Kristen A. Rodrigues

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

SUMMARY Rare B cells can have special pathogen-recognition features giving them the potential to make outsized contributions protective immunity. However, rare naive infrequently participate in immune responses. We investigated how germline-targeting vaccine antigen delivery and adjuvant selection affect priming of exceptionally BG18-like HIV broadly neutralizing antibody-precursor (~1 50 million) non-human primates. Only escalating dose (ED) immunization using saponin SMNP elicited detectable germinal centers (GCs). All groups had strong GC responses, but only ED+SMNP bolus+SMNP induced memory >50% animals. One group vaccine-specific responses equivalent ED+SMNP, were rarely detected. Following homologous boosting, more frequent a bolus group, lower somatic hypermutation affinities. This outcome was inversely associated with post-prime antibody titers, suggesting feedback significantly influence precursor cell

Language: Английский

Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates DOI
Jon M. Steichen, Ivy Phung, Eugenia Salcedo

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6697)

Published: May 16, 2024

Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, vaccine priming HCDR3-dominant bnAbs germline-targeting has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an envelope trimer designed target precursors bnAb BG18, primed bnAb-precursor B cells eight rhesus macaques substantial frequencies diverse lineages germinal center memory cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions cryo-electron microscopy. Our results demonstrate proof principle animals suggest that N332-GT5 holds similar responses humans.

Language: Английский

Citations

20
Progress and Challenges in HIV-1 Vaccine Research: A Comprehensive Overview DOI Creative Commons
Alex Boomgarden, Chitra Upadhyay

Vaccines, Journal Year: 2025, Volume and Issue: 13(2), P. 148 - 148

Published: Jan. 31, 2025

The development of an effective HIV-1 vaccine remains a formidable challenge in biomedical research. Despite significant advancements our understanding HIV biology and pathogenesis, progress has been impeded by factors such as the virus's genetic diversity, high mutation rates, its ability to establish latent reservoirs. Recent innovative approaches, including mosaic vaccines mRNA technology induce broadly neutralizing antibodies, have shown promise. However, efficacy these modest, with best results achieving approximately 30% effectiveness. Ongoing research emphasizes necessity multifaceted strategy overcome obstacles achieve breakthrough development. This review summarizes current approaches utilized further understand create global vaccine. We discuss impact on for other diseases, COVID-19, influenza, Zika virus. Additionally, we highlight specific limitations faced each approach present methods researchers employ challenges. These techniques, which demonstrated preclinical clinical success, advanced field closer ultimate goal developing Leveraging will enable strides combating infectious ultimately improving health outcomes.

Language: Английский

Citations

3
RNA-lipid nanoparticle therapeutics for women’s health DOI Creative Commons
Alireza Nomani,

Aishwarya Saraswat,

Yu Zhang

et al.

Frontiers in Nanotechnology, Journal Year: 2025, Volume and Issue: 7

Published: March 19, 2025

Ribonucleic acid-lipid nanoparticle (RNA-LNP) therapeutics, a powerful nanomedicine platform, have already demonstrated their efficacy in diverse applications. Their improved stability and are exemplified by successful rapid launch of mRNA vaccines, as well marketed siRNA drug product. Beyond infectious diseases, RNA-LNPs show promise addressing unmet needs women’s health, for instance, gynecologic cancers (e.g., ovarian, cervical) novel treatments conditions such osteoporosis, endometriosis, congenital disorders. However, important challenges persist, including off-target effects, immunogenicity, potential risks ethical issues application pregnant or lactating women. This review summarizes current key preclinical clinical progress, discusses targeting strategies LNPs active passive delivery), presents knowledge on RNA-LNP safety non-pregnant women neonates vulnerable populations. As technologies evolve – with relevant animal models, next-generation RNA platforms lipid chemistries they can hold significant transforming care health through safer, effective, personalized, innovative curative interventions.

Language: Английский

Citations

1
Recent Advancements in mRNA Vaccines: From Target Selection to Delivery Systems DOI Creative Commons
Zhongyan Wu,

Weilu Sun,

Hailong Qi

et al.

Vaccines, Journal Year: 2024, Volume and Issue: 12(8), P. 873 - 873

Published: Aug. 1, 2024

mRNA vaccines are leading a medical revolution. technologies utilize the host's own cells as bio-factories to produce proteins that serve antigens. This revolutionary approach circumvents complicated processes involved in traditional vaccine production and empowers with ability respond emerging or mutated infectious diseases rapidly. Additionally, robust cellular immune response elicited by has shown significant promise cancer treatment. However, inherent instability of complexity tumor immunity have limited its broader application. Although emergence pseudouridine ionizable cationic lipid nanoparticles (LNPs) made clinical application possible, there remains substantial potential for further improvement immunogenicity delivered antigens preventive therapeutic effects technology. Here, we review latest advancements vaccines, including but not target selection delivery systems. offers multifaceted perspective on this rapidly evolving field.

Language: Английский

Citations

9
mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models DOI Open Access
Xuesong Wang, Christopher A. Cottrell, Xiaozhen Hu

et al.

Science Immunology, Journal Year: 2024, Volume and Issue: 9(95)

Published: May 10, 2024

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 be simultaneously primed and undergo diversification affinity maturation without exclusionary competition. Boosts drove precursor participation germinal centers; accumulation somatic hypermutations, including key positions; boost native-like antigens two lineages. We prime-boost regimen nanoparticles encoded by mRNA-LNP, demonstrating that multiple can primed, boosted, diversified along bnAb pathway.

Language: Английский

Citations

8
mRNA vaccines in tumor targeted therapy: mechanism, clinical application, and development trends DOI Creative Commons
Yu Gao,

Liang Yang,

Zhenning Li

et al.

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Aug. 31, 2024

Abstract Malignant tumors remain a primary cause of human mortality. Among the various treatment modalities for neoplasms, tumor vaccines have consistently shown efficacy and promising potential. These offer advantages such as specificity, safety, tolerability, with mRNA representing platforms. By introducing exogenous mRNAs encoding antigens into somatic cells subsequently synthesizing through gene expression systems, can effectively induce immune responses. Katalin Karikó Drew Weissman were awarded 2023 Nobel Prize in Physiology or Medicine their great contributions to vaccine research. Compared traditional vaccines, several advantages, including rapid preparation, reduced contamination, nonintegrability, high biodegradability. Tumor-targeted therapy is an innovative modality that enables precise targeting cells, minimizes damage normal tissues, safe at doses, demonstrates efficacy. Currently, targeted has become important option malignant tumors. The application tumor-targeted expanding, numerous clinical trials underway. We systematically outline delivery mechanism by which anti-tumor responses, describe current research applications therapy, forecast future development trends therapy.

Language: Английский

Citations

8
Broadly inhibitory antibodies to severe malaria virulence proteins DOI
Raphael A. Reyes, Sai Sundar Rajan Raghavan, Nicholas K. Hurlburt

et al.

Nature, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Language: Английский

Citations

8
Progress on priming HIV-1 immunity DOI
Rogier W. Sanders, John P. Moore

Science, Journal Year: 2024, Volume and Issue: 384(6697), P. 738 - 739

Published: May 16, 2024

Four new studies inform on the multistep path to generate broadly active HIV-1 antibodies

Language: Английский

Citations

7
Developing mRNA Nanomedicines with Advanced Targeting Functions DOI Creative Commons
Ji Wang, Lijun Cai, Ning Li

et al.

Nano-Micro Letters, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 21, 2025

The emerging messenger RNA (mRNA) nanomedicines have sprung up for disease treatment. Developing targeted mRNA has become a thrilling research hotspot in recent years, as they can be precisely delivered to specific organs or tissues enhance efficiency and avoid side effects. Herein, we give comprehensive review on the latest progress of with targeting functions. its carriers are first described detail. Then, mechanisms passive targeting, endogenous active outlined, focus various biological barriers that may encounter during vivo delivery. Next, emphasis is placed summarizing mRNA-based organ-targeting strategies. Lastly, advantages challenges clinical translation mentioned. This expected inspire researchers this field drive further development technology.

Language: Английский

Citations

1
Interventions during Early Infection: Opening a Window for an HIV Cure? DOI Creative Commons
Christopher R. Hiner, April L. Mueller, Hang Su

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(10), P. 1588 - 1588

Published: Oct. 9, 2024

Although combination antiretroviral therapy (ART) has been a landmark achievement for the treatment of human immunodeficiency virus (HIV), an HIV cure remained elusive. Elimination latent reservoirs that persist throughout infection is most challenging barrier to cure. The progressive marked by increasing size and diversity until effective immune response mobilized, which can control but not eliminate infection. stalemate between replication manifested establishment viral set point. ART initiation during early stage limits reservoir development, preserves function, improves quality life, may lead ART-free remission in few people living with (PLWH). However, overwhelming majority PLWH, alone does HIV, lifelong needed sustain suppression. A critical area research focused on determining whether could be functionally cured if additional treatments are provided alongside ART. Several interventions including Block Lock, Shock Kill, broadly neutralizing antibody (bNAb) therapy, adoptive CD8+ T cell gene have demonstrated delayed rebound and/or animal models some PLWH. Whether or their application improve success less studied. Herein, we review current state clinical investigative discuss potential likelihood post-treatment initiated

Language: Английский

Citations

3