Cited by Diverse priming outcomes under conditions of very rare precursor B cells

mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies DOI

Zhenfei Xie, Ying‐Cing Lin, Jon M. Steichen

et al.

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

Published: May 16, 2024

Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody–induced epitope masking, driving further cell receptor (BCR) modification in GC-experienced after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors V3-glycan–targeted bnAb BG18 primed were effectively boosted either two novel immunogens designed have minimum cross-reactivity with off-target V1-binding responses. The delivery messenger RNA lipid nanoparticles (mRNA-LNPs) generated long-lasting GCs, somatic hypermutation, affinity maturation an effective tool development.

Language: Английский

Citations

Linking vaccine adjuvant mechanisms of action to function DOI

Elana Ben‐Akiva, Asheley P. Chapman, Tianyang Mao

et al.

Science Immunology, Journal Year: 2025, Volume and Issue: 10(104)

Published: Feb. 14, 2025

Vaccines deliver an immunogen in a manner designed to safely provoke immune response, leading the generation of memory T and B cells long-lived antibody-producing plasma cells. Adjuvants play critical role vaccines by controlling how system is exposed providing inflammatory cues that enable productive priming. However, mechanisms action underlying adjuvant function at molecular, cell, tissue levels are diverse often poorly understood. Here, we review current understanding adjuvants used subunit protein/polysaccharide mRNA vaccines, discuss where possible these link downstream effects on identify knowledge gaps will be important fill order continued development more effective for challenging pathogens such as HIV emerging threats.

Language: Английский

Citations

Two-dose priming immunization amplifies humoral immunity by synchronizing vaccine delivery with the germinal center response DOI

Sachin Bhagchandani, Leerang Yang, Jonathan Lam

et al.

Science Immunology, Journal Year: 2024, Volume and Issue: 9(99)

Published: Sept. 20, 2024

Prolonging exposure to subunit vaccines during the primary immune response enhances humoral immunity. Escalating-dose immunization (EDI), administering every other day in an increasing pattern over 2 weeks, is particularly effective but challenging implement clinically. Here, using HIV Env trimer/saponin adjuvant vaccine, we explored simplified EDI regimens and found that a two-shot regimen 20% of vaccine followed by remaining 80% dose 7 days later increased T

Language: Английский

Citations

mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models DOI

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

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

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

A Spleen‐Targeted Tolerogenic mRNA‐LNPs Vaccine for the Treatment of Experimental Asthma DOI

Fazhan Wang,

Jia Lou,

Xiaohan Lou

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Lipid nanoparticles (LNPs)-based mRNA vaccines have witnessed their great advantages in the fight against infectious diseases. However, pro-inflammatory properties of mRNA-LNPs may hinder induction antigen-specific tolerogenic immune responses. Here, it is demonstrated that stearic acid-doped LNPs co-loaded with nucleoside-modified and celastrol selectively target spleen, convert adjuvanticity promote a rather than immunogenic DCs phenotype. Furthermore, vaccine also invokes generation regulatory T cells (Tregs) spleen migration induced Tregs to lung. In mouse model allergic asthma, immunization significantly alleviated symptom induction, reducing eosinophilic granulocyte accumulation mucus secretion. conclusion, this spleen-targeted platform induces responses, offering promise for development therapeutics asthma other conditions requiring tolerance modulation.

Language: Английский

Citations

Dose-dependent regulation of immune memory responses against HIV by saponin monophosphoryl lipid A nanoparticle adjuvant DOI

Parham Ramezani-Rad,

Ester Marina-Zárate, Laura Maiorino

et al.

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

Published: Aug. 3, 2024

Abstract 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 establishment Env-specific memory T B cell (T Mem ) long-lived plasma cells non-human primates. Robust were detected all groups, but 6-fold increase was observed highest SMNP group vs. lowest group. Similarly, stronger induced for CD40L + OX40 CD4 (11-fold), IFNγ (15-fold), IL21 (9-fold), circulating FH (3.6-fold), bone marrow (7-fold), binding IgG (1.3-fold). Substantial tier-2 neutralizing antibodies only higher groups. These investigations highlight dose-dependent potency primates, which are relevant human next-generation

Language: Английский

Citations

HIV Vaccine Development at a Crossroads: New B and T Cell Approaches DOI

Ramesh Govindan, Kathryn E. Stephenson

Vaccines, Journal Year: 2024, Volume and Issue: 12(9), P. 1043 - 1043

Published: Sept. 12, 2024

Despite rigorous scientific efforts over the forty years since onset of global HIV pandemic, a safe and effective HIV-1 vaccine remains elusive. The challenges development have proven immense, in large part due to tremendous sequence diversity its ability escape from antiviral adaptive immune responses. In recent years, several phase 3 efficacy trials been conducted, testing similar hypothesis, e.g., that non-neutralizing antibodies classical cellular responses could prevent acquisition. These studies were not successful. As result, field has now pivoted bold novel approaches, including sequential immunization strategies drive generation broadly neutralizing human CMV-vectored vaccines elicit MHC-E-restricted CD8+ T cell Many these candidates are 1 trials, with early promising results.

Language: Английский

Citations

An engineered immunogen activates diverse HIV broadly neutralizing antibody precursors and promotes acquisition of improbable mutations DOI

Olivia Swanson, Qianyi E. Zhang, Elizabeth Van Itallie

et al.

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(780)

Published: Jan. 8, 2025

Elicitation of HIV broadly neutralizing antibodies (bnAbs) by vaccination first requires the activation diverse precursors, followed successive boosts that guide these responses to enhanced breadth through acquisition somatic mutations. Because bnAbs contain mutations in their B cell receptors (BCRs) are rarely generated during conventional maturation, vaccine immunogens must robustly engage and expand cells with BCRs improbable Here, we engineered an immunogen activates precursors V3-glycan bnAb promotes a functionally critical mutation. This was validated biochemically, structurally, three different humanized immunoglobulin mouse models were designed test immunogens. These results provide blueprint for rationally designing priming explicitly target elicitation functional yet

Language: Английский

Citations