Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains ("arms") radiating from a central dendrimer unit ("core") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, in vivo studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.

• MeSH
• dendrimery * chemie   MeSH
• lidé MeSH
• myši MeSH
• nosiče léků chemie   MeSH
• polyaminy MeSH
• polymery chemie   MeSH
• vakcíny proti AIDS imunologie   chemie   aplikace a dávkování   MeSH
• vakcíny imunologie   chemie   aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dendrimery * MeSH
• nosiče léků MeSH
• Poly(amidoamine) MeSH Prohlížeč
• polyaminy MeSH
• polymery MeSH
• vakcíny proti AIDS MeSH
• vakcíny MeSH

Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen-specific humoral and cellular immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the human immunodeficiency virus or to induce cellular T-cell immunity in the fight against cancer. The recent SARS-CoV-2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan-coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as "tumor-associated carbohydrate antigens". Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T-cell-independent antigens, not eliciting protective immunoglobulin G responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy.

• Klíčová slova
• cancer, glycosylation, immune system, infection, vaccination,
• MeSH
• COVID-19 * prevence a kontrola   MeSH
• glykokonjugáty terapeutické užití   MeSH
• lidé MeSH
• nádory * prevence a kontrola   MeSH
• polysacharidy terapeutické užití   MeSH
• SARS-CoV-2 MeSH
• vakcíny * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• glykokonjugáty MeSH
• polysacharidy MeSH
• vakcíny * MeSH

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.

• Klíčová slova
• FDG Abs, Fab dimerization, HIV-1 Env glycans, IgM-memory B cells, SARS-CoV-2 spike glycans, glycan-dependent Ab binding, marginal zone B cells, natural Abs,
• MeSH
• B-lymfocyty imunologie   MeSH
• COVID-19 imunologie   MeSH
• dimerizace MeSH
• epitopy imunologie   MeSH
• genové produkty env - virus lidské imunodeficience chemie   genetika   imunologie   MeSH
• glykoprotein S, koronavirus imunologie   MeSH
• glykosylace MeSH
• HIV infekce imunologie   MeSH
• HIV protilátky imunologie   MeSH
• HIV-1 imunologie   MeSH
• imunoglobuliny - Fab fragmenty chemie   imunologie   MeSH
• lidé MeSH
• Macaca mulatta MeSH
• neutralizující protilátky imunologie   MeSH
• polysacharidy chemie   imunologie   MeSH
• receptory antigenů B-buněk chemie   MeSH
• SARS-CoV-2 imunologie   MeSH
• široce neutralizující protilátky imunologie   MeSH
• vakcíny imunologie   MeSH
• virus opičí imunodeficience genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• epitopy MeSH
• genové produkty env - virus lidské imunodeficience MeSH
• glykoprotein S, koronavirus MeSH
• HIV protilátky MeSH
• imunoglobuliny - Fab fragmenty MeSH
• neutralizující protilátky MeSH
• polysacharidy MeSH
• receptory antigenů B-buněk MeSH
• široce neutralizující protilátky MeSH
• spike protein, SARS-CoV-2 MeSH Prohlížeč
• vakcíny MeSH

Viral infections have recently emerged not only as a health threat to people but rapidly became the cause of universal fatality on a large scale. Nanomaterials comprising functionalized nanoparticles (NPs) and quantum dots and nanotechnology-associated innovative detection methods, vaccine design, and nanodrug production have shown immense promise for interfacing with pathogenic viruses and restricting their entrance into cells. These viruses have been scrutinized using rapid diagnostic detection and therapeutic interventional options against the caused infections including vaccine development for prevention and control. Coronaviruses, namely SARS-CoV, MERS-CoV, and SARS-CoV-2, have endangered human life, and the COVID-19 (caused by SARS-CoV-2) outbreak has become a perilous challenge to public health globally with huge accompanying morbidity rates. Thus, it is imperative to expedite the drug and vaccine development efforts that would help mitigate this pandemic. In this regard, smart and innovative nano-based technologies and approaches encompassing applications of green nanomedicine, bio-inspired methods, multifunctional bioengineered nanomaterials, and biomimetic drug delivery systems/carriers can help resolve the critical issues regarding detection, prevention, and treatment of viral infections. This perspective review expounds recent nanoscience advancements for the detection and treatment of viral infections with focus on coronaviruses and encompasses nano-based formulations and delivery platforms, nanovaccines, and promising methods for clinical diagnosis, especially regarding SARS-CoV-2.

• Klíčová slova
• COVID-19, SARS-CoV-2, coronaviruses, graphene oxide, nanoparticles, nanotechnology, nanovaccines, quantum dots, viral infections,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

A growing global health concern, Lyme disease has become the most common tick-borne disease in the United States and Europe. Caused by the bacterial spirochete Borrelia burgdorferi sensu lato (sl), this disease can be debilitating if not treated promptly. Because diagnosis is challenging, prevention remains a priority; however, a previously licensed vaccine is no longer available to the public. Here, we designed a six component vaccine that elicits antibody (Ab) responses against all Borrelia strains that commonly cause Lyme disease in humans. The outer surface protein A (OspA) of Borrelia was fused to a bacterial ferritin to generate self-assembling nanoparticles. OspA-ferritin nanoparticles elicited durable high titer Ab responses to the seven major serotypes in mice and non-human primates at titers higher than a previously licensed vaccine. This response was durable in rhesus macaques for more than 6 months. Vaccination with adjuvanted OspA-ferritin nanoparticles stimulated protective immunity from both B. burgdorferi and B. afzelii infection in a tick-fed murine challenge model. This multivalent Lyme vaccine offers the potential to limit the spread of Lyme disease.

• Klíčová slova
• Immunology, Infectious diseases, Vaccines,
• Publikační typ
• časopisecké články MeSH

Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.

• MeSH
• adjuvancia imunologická chemie   MeSH
• antigeny nádorové imunologie   MeSH
• CD8-pozitivní T-lymfocyty metabolismus   MeSH
• individualizovaná medicína MeSH
• melanom experimentální farmakoterapie   imunologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanočástice MeSH
• primáti MeSH
• protinádorové vakcíny aplikace a dávkování   imunologie   MeSH
• toll-like receptor 7 imunologie   MeSH
• toll-like receptor 8 imunologie   MeSH
• vakcinace MeSH
• vakcíny konjugované MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• antigeny nádorové MeSH
• protinádorové vakcíny MeSH
• toll-like receptor 7 MeSH
• toll-like receptor 8 MeSH
• vakcíny konjugované MeSH

Patients with inadequate anti-cancer T cell responses experience limited benefit from immune checkpoint inhibitors and other immunotherapies that require T cells. Therefore, treatments that induce de novo anti-cancer T cell immunity are needed. One strategy - referred to as in situ vaccination - is to deliver chemotherapeutic or immunostimulatory drugs into tumors to promote cancer cell death and provide a stimulatory environment for priming T cells against antigens already present in the tumor. However, achieving sufficient drug concentrations in tumors without causing dose-limiting toxicities remains a major challenge. To address this challenge, nanomedicines based on nano-sized carriers ('nanocarriers') of chemotherapeutics and immunostimulants are being developed to improve drug accumulation in tumors following systemic (intravenous) administration. Herein, we present the rationale for using systemically administrable nanomedicines to induce anti-cancer T cell immunity via in situ vaccination and provide an overview of synthetic nanomedicines currently used clinically. We also describe general strategies for improving nanomedicine design to increase tumor uptake, including use of micelle- and star polymer-based nanocarriers. We conclude with perspectives for how nanomedicine properties, host factors and treatment combinations can be leveraged to maximize efficacy.

• Klíčová slova
• Chemotherapeutic and immunostimulant, Immunogenic cell death, Nanomedicine and biomaterials, Nanoparticle and microparticle, Pattern recognition receptor,
• MeSH
• adjuvancia imunologická aplikace a dávkování   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• nádory farmakoterapie   imunologie   terapie   MeSH
• nanomedicína metody   MeSH
• protinádorové vakcíny aplikace a dávkování   imunologie   MeSH
• T-lymfocyty účinky léků   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• protinádorové vakcíny MeSH

Peptide immunogens provide an approach to focus antibody responses to specific neutralizing sites on the HIV envelope protein (Env) trimer or on other pathogens. However, the physical characteristics of peptide immunogens can limit their pharmacokinetic and immunological properties. Here, we have designed synthetic "star" nanoparticles based on biocompatible N-[(2-hydroxypropyl)methacrylamide] (HPMA)-based polymer arms extending from a poly(amidoamine) (PAMAM) dendrimer core. In mice, these star nanoparticles trafficked to lymph nodes (LNs) by 4 hours following vaccination, where they were taken up by subcapsular macrophages and then resident dendritic cells (DCs). Immunogenicity optimization studies revealed a correlation of immunogen density with antibody titers. Furthermore, the co-delivery of Env variable loop 3 (V3) and T-helper peptides induced titers that were 2 logs higher than if the peptides were given in separate nanoparticles. Finally, we performed a nonhuman primate (NHP) study using a V3 glycopeptide minimal immunogen that was structurally optimized to be recognized by Env V3/glycan broadly neutralizing antibodies (bnAbs). When administered with a potent Toll-like receptor (TLR) 7/8 agonist adjuvant, these nanoparticles elicited high antibody binding titers to the V3 site. Similar to human V3/glycan bnAbs, certain monoclonal antibodies (mAbs) elicited by this vaccine were glycan dependent or targeted the GDIR peptide motif. To improve affinity to native Env trimer affinity, nonhuman primates (NHPs) were boosted with various SOSIP Env proteins; however, significant neutralization was not observed. Taken together, this study provides a new vaccine platform for administration of glycopeptide immunogens for focusing immune responses to specific bnAb epitopes.

• MeSH
• epitopy imunologie   MeSH
• HIV infekce imunologie   MeSH
• HIV obalový protein gp120 chemie   MeSH
• HIV séropozitivita imunologie   MeSH
• HIV-1 imunologie   MeSH
• Macaca mulatta MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nanočástice chemie   terapeutické užití   MeSH
• neutralizující protilátky imunologie   MeSH
• peptidy MeSH
• primáti MeSH
• tvorba protilátek imunologie   MeSH
• vakcíny proti AIDS imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• epitopy MeSH
• HIV obalový protein gp120 MeSH
• neutralizující protilátky MeSH
• peptidy MeSH
• vakcíny proti AIDS MeSH