Oral Immunization remains a challenge as antigens are rapidly metabolized in the gastrointestinal tract. In numerous previous studies, Self-emulsifying drug delivery systems (SEDDS) have demonstrated to be a promising tool for oral delivery of biologics. In this study, the potential of SEDDS as vehicle for oral vaccination has been evaluated. At this purpose, the model antigen Bovine serum albumin (BSA) has been incorporated in SEDDS after ion pairing. Squalane and monophosphoryl lipid A (MPLA) were chosen as adjuvants and dissolved in SEDDS containing BSA (SEDDS-BSA-squalane and SEDDS-BSA-MPLA). Formulations were administered orally to BALB/c mice. As control unformulated BSA was administrated orally (BSA-oral) and subcutaneously (BSA-sc). Systemic (anti BSA IgG titre) and mucosal (anti BSA IgA titre) immugenicity of BSA loaded in SEDDS and of unformulated BSA administered orally and subcutaneously was assessed and compared with each other. SEDDS-BSA-squalane and SEDDS-BSA-MPLA induced both higher anti BSA-IgG titre and anti BSA-IgA titre than orally administered unformulated BSA. BSA-sc induced the highest systemic immune response, however, the highest mucosal immune response was achieved via oral administration of SEDDS-BSA-squalane and SEDDS-BSA-MPLA. In general, SEDDS-BSA-MPLA showed the most promising systemic and mucosal immune response. According to these results, SEDDS seems to be a promising carrier for oral delivery of vaccines. STATEMENT OF SIGNIFICANCE: Oral vaccination is still a great challenge, as orally administered antigens are easily degraded in the gastrointestinal (GI) tract by peptidases and proteases. During the last years, self-emulsifying drug delivery systems (SEDDS) consisting of a mixture of oils and surfactants have been developed for the oral administration of hydrophilic macromolecular drugs. In this study, Bovine serum albumin (BSA) was chosen as model antigen and incorporated into self-emulsifying drug delivery systems (SEDDS) after hydrophobic ion pairing. Lipid A from Salmonella Minnesota R595 (MPLA) and squalane were chosen as adjuvants. SEDDS-BSA-MPLA and SEDDS-BSA-squalane were administered orally to mice. SEDDS-BSA-MPLA induced the strongest systemic (anti BSA-IgG titre) and mucosal (anti BSA-IgA titre) immune response. Based on these results, SEDDS are a promising alternative carrier for oral vaccine delivery.

• MeSH
• aplikace orální MeSH
• emulze MeSH
• imunoglobulin G imunologie   MeSH
• lipid A analogy a deriváty   chemie   farmakologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• sérový albumin hovězí * chemie   imunologie   farmakologie   MeSH
• systémy cílené aplikace léků * MeSH
• vakcinace * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Positive selection acting on Toll-like receptors (TLRs) has been recently investigated to reveal evolutionary mechanisms of host-pathogen molecular co-adaptation. Much of this research, however, has focused mainly on the identification of sites predicted to be under positive selection, bringing little insight into the functional differences and similarities among species and a limited understanding of convergent evolution in the innate immune molecules. In this study, we provide evidence of phenotypic variability in the avian TLR4 ligand-binding region (LBR), the direct interface between host and pathogen molecular structures. We show that 55 passerine species vary substantially in the distribution of electrostatic potential on the surface of the receptor, and based on these distinct patterns, we identified four species clusters. Seven of the 34 evolutionarily nonconservative and positively selected residues correspond topologically to sites previously identified as being important for lipopolysaccharide, lipid IVa or MD-2 binding. Five of these positions codetermine the identity of the charge clusters. Groups of species that host-related communities of pathogens were predicted to cluster based on their TLR4 LBR charge. Despite some evidence for convergence among taxa, there were no clear associations between the TLR4 LBR charge distribution and any of the general ecological characteristics compared (migration, latitudinal distribution and diet). Closely related species, however, mostly belonged to the same surface charge cluster indicating that phylogenetic constraints are key determinants shaping TLR4 adaptive evolution. Our results suggest that host innate immune evolution is consistent with Fahrenholz's rule on the cospeciation of hosts and their parasites.

• MeSH
• glykolipidy chemie   genetika   MeSH
• interakce hostitele a patogenu genetika   MeSH
• konformace proteinů MeSH
• ligandy MeSH
• lipid A analogy a deriváty   chemie   genetika   MeSH
• lipopolysacharidy chemie   genetika   MeSH
• lymfocytární antigen 96 chemie   genetika   MeSH
• mikrobiota genetika   MeSH
• molekulární evoluce * MeSH
• molekulární modely MeSH
• přirozená imunita genetika   MeSH
• ptáci genetika   parazitologie   MeSH
• sekvenční analýza DNA MeSH
• selekce (genetika) * genetika   MeSH
• statická elektřina MeSH
• toll-like receptor 4 chemie   genetika   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Background: The herpes zoster subunit vaccine (HZ/su), consisting of varicella-zoster virus glycoprotein E (gE) and AS01B Adjuvant System, was highly efficacious in preventing herpes zoster in the ZOE-50 and ZOE-70 trials. We present immunogenicity results from those trials. Methods: Participants (ZOE-50: ≥50; ZOE-70: ≥70 years of age) received 2 doses of HZ/su or placebo, 2 months apart. Serum anti-gE antibodies and CD4 T cells expressing ≥2 of 4 activation markers assessed (CD42+) after stimulation with gE-peptides were measured in subcohorts for humoral (n = 3293) and cell-mediated (n = 466) immunogenicity. Results: After vaccination, 97.8% of HZ/su and 2.0% of placebo recipients showed a humoral response. Geometric mean anti-gE antibody concentrations increased 39.1-fold and 8.3-fold over baseline in HZ/su recipients at 1 and 36 months post-dose 2, respectively. A gE-specific CD42+ T-cell response was shown in 93.3% of HZ/su and 0% of placebo recipients. Median CD42+ T-cell frequencies increased 24.6-fold (1 month) and 7.9-fold (36 months) over baseline in HZ/su recipients and remained ≥5.6-fold above baseline in all age groups at 36 months. The proportion of CD4 T cells expressing all 4 activation markers increased over time in all age groups. Conclusions: Most HZ/su recipients developed robust immune responses persisting for 3 years following vaccination. Clinical Trials Registration: NCT01165177; NCT01165229.

• MeSH
• adjuvancia imunologická farmakologie   MeSH
• buněčná imunita imunologie   MeSH
• CD4-pozitivní T-lymfocyty MeSH
• herpes zoster imunologie   MeSH
• humorální imunita imunologie   MeSH
• imunogenicita vakcíny imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipid A analogy a deriváty   farmakologie   MeSH
• proteiny virového obalu imunologie   MeSH
• protilátky virové imunologie   MeSH
• saponiny farmakologie   MeSH
• senioři MeSH
• subjednotkové vakcíny imunologie   MeSH
• vakcína proti pásovému oparu imunologie   MeSH
• vakcinace metody   MeSH
• virus varicella zoster imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: In adults aged ≥60 years, two doses of the herpes zoster subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01B Adjuvant System) elicited humoral and cell-mediated immune responses persisting for at least six years. We assessed immunogenicity nine years post-initial vaccination. METHODS: This open extension study (NCT02735915) followed 70 participants who received two HZ/su doses in the initial trial (NCT00434577). Blood samples to assess the cellular (intracellular cytokine staining) and humoral (ELISA) immunity were taken at year nine post-initial vaccination. RESULTS: Participants' mean age at dose 1 was 72.3 years. The fold increases over pre-vaccination in the mean frequency of gE-specific CD4+ T-cells expressing ≥2 activation markers plateaued from year four post-dose 1 until year nine. Anti-gE antibody geometric mean concentrations plateaued and remained above pre-vaccination levels from year four onwards. Immunogenicity at year nine was similar across age strata (60-69, ≥70 years) and confirmed statistical prediction model results using data for up to year six. Further modeling using all data up to year nine predicted immune responses would remain above the pre-vaccination level up to year 15. CONCLUSION: In adults aged ≥60 years, HZ/su-induced immunogenicity remained above pre-vaccination levels for at least nine years post-initial vaccination. SUMMARY: After vaccination with HZ/su, both cell mediated and humoral immunity remained above pre-vaccination levels up to year 9 regardless of age group. Immune responses are predicted to remain above baseline up to 15 years post initial vaccination.

• MeSH
• časové faktory MeSH
• cytokiny analýza   MeSH
• dospělí MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipid A aplikace a dávkování   analogy a deriváty   MeSH
• následné studie MeSH
• protilátky virové krev   MeSH
• saponiny aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• subjednotkové vakcíny aplikace a dávkování   imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• vakcína proti pásovému oparu aplikace a dávkování   imunologie   MeSH
• virus varicella zoster imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH

BACKGROUND: An investigational subunit vaccine containing the varicella-zoster virus (VZV) glycoprotein E (gE) and the AS01B adjuvant system is being evaluated for the prevention of herpes zoster (HZ) in older adults. A phase II trial evaluating different formulations of this vaccine (containing 25μg, 50μg, or 100μg gE) was conducted in adults ≥60 years of age and showed that all formulations elicited robust cellular and humoral immune responses for up to 3 years after vaccination. In this follow-up study in subjects who received two doses of the 50μg gE/AS01B formulation (HZ/su), we assessed the persistence of the immune responses for up to 6 years after vaccination. METHODS: This phase II, open-label, multicenter, single-group trial conducted in the Czech Republic, Germany, Sweden, and the Netherlands followed 129 subjects who had received two doses (2 months apart) of HZ/su during the initial trial. Vaccine-induced immune responses (frequencies of gE-specific CD4(+) T cells expressing ≥2 activation markers and serum anti-gE antibody concentrations) were evaluated at 48, 60, and 72 months after the first HZ/su dose. RESULTS: Six years after vaccination with HZ/su, gE-specific cell-mediated immune responses and anti-gE antibody concentrations had decreased by 20-25% from month 36, but remained higher than the prevaccination values. At month 72, the gE-specific cell-mediated immune response was 3.8 times higher than the prevaccination value (477.3 vs. 119.4 activated gE-specific CD4(+) T cells per 10(6) cells), and the anti-gE antibody concentration was 7.3 times higher than the prevaccination value (8159.0 vs. 1121.3mIU/mL). No vaccine-related serious adverse events were reported between months 36 and 72. CONCLUSIONS: gE-specific cellular and humoral immune responses persisted for 6 years after two-dose vaccination with HZ/su in healthy older adults. No safety concerns were identified.

• MeSH
• buněčná imunita * MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• fixní kombinace léků MeSH
• herpes zoster prevence a kontrola   MeSH
• humorální imunita * MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipid A aplikace a dávkování   analogy a deriváty   MeSH
• následné studie MeSH
• proteiny virového obalu imunologie   MeSH
• protilátky virové krev   MeSH
• saponiny aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• subjednotkové vakcíny imunologie   terapeutické užití   MeSH
• vakcína proti pásovému oparu imunologie   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• MeSH
• adenosin analogy a deriváty   aplikace a dávkování   škodlivé účinky   MeSH
• alergická rýma imunologie   terapie   MeSH
• antialergika farmakologie   terapeutické užití   MeSH
• bronchiální astma imunologie   terapie   MeSH
• cílená molekulární terapie MeSH
• desenzibilizace imunologická metody   MeSH
• fenylacetáty aplikace a dávkování   škodlivé účinky   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• lipid A analogy a deriváty   aplikace a dávkování   škodlivé účinky   MeSH
• oligodeoxyribonukleotidy aplikace a dávkování   škodlivé účinky   MeSH
• oligonukleotidy aplikace a dávkování   škodlivé účinky   MeSH
• toll-like receptory agonisté   imunologie   MeSH
• vakcíny aplikace a dávkování   škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

• Klíčová slova
• Cervarix, ASO4, bivalentní HPV vakcína, dvoudávkové schéma HPV vakcinace, studie HPV 048, studie HPV 070,
• MeSH
• Alphapapillomavirus genetika   klasifikace   MeSH
• časové faktory MeSH
• dítě MeSH
• hydroxid hlinitý MeSH
• infekce papilomavirem imunologie   prevence a kontrola   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• lidský papilomavirus 16 genetika   imunologie   MeSH
• lidský papilomavirus 18 genetika   imunologie   MeSH
• lipid A analogy a deriváty   MeSH
• mladiství MeSH
• nádory děložního čípku prevence a kontrola   MeSH
• očkovací schéma MeSH
• přehodnocení terapeutických indikací léčivého přípravku MeSH
• protilátky virové imunologie   krev   MeSH
• randomizované kontrolované studie jako téma MeSH
• terapeutická ekvivalence MeSH
• tvorba protilátek imunologie   MeSH
• vakcinace metody   MeSH
• vakcíny proti papilomavirům aplikace a dávkování   chemie   imunologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Očkovací látky proti lidskému papilomaviru (HPV) byly vytvářeny na základě detailních znalostí imunologie, genetiky, virologie a patofyziologie papilomavirové infekce. Vakcína Cervarix proti onkogenním typům HPV 16 a HPV 18 obsahuje 20 µg antigenů L1 obou typů a je formulována s adjuvantním systémem AS04, který se skládá z 50 µg monofosforyl lipidu A adsorbovaného na 500 µg aluminium hydroxidu. Antigen vakcíny je nejen deponován v místě vpichu díky soli aluminia a tak se pomalu a déle uvolňuje pro buňky prezentující antigen, ale zároveň vydává pro imunitní systém „signál nebezpečí“ pomocí monofosforyl lipidu A, který se naváže na toll-like receptor-4. Vakcína s AS04 díky kombinovanému účinku antigenů a AS04 zvyšuje hladinu neutralizačních protilátek v séru i na cervikovaginální sliznici, podporuje tvorbu vyšších koncentrací specifických B lymfocytů, posiluje T lymfocytární, tedy dlouhodobou, paměť a zajišťuje zkříženou protekci i proti nevakcinálním HPV typům. Vakcína je tak schopná ochránit až 93,2 % HPV naivních dívek v porovnání s kontrolní skupinou, a to bez ohledu na nukleové kyseliny viru v lézi. Bezpečnostní profil vakcíny je výborný.

Vaccines against human papillomavirus (HPV) have been developed on the basis of detailed knowledge of immunology, genetics, virology and pathophysiology of the papillomavirus infection. The vaccine Cervarix, developed against HPV types 16 and 18, contains 20 mcg of antigen L1 of both types and it is formulated with the AS04 adjuvant system, which consists of 50 mcg of monophosphoryl lipid A adsorbed into 500 mcg of aluminum hydroxide. Thanks to aluminium salts, the antigen is not deposited only at the site and thus releases the antigen more slowly for the presenting cells, but also gives the immune system a pathogen-associated molecular pattern signal using monophosphoryl lipid A, which binds to toll-like receptor-4. Due to the combined effect of the vaccine antigens and AS04, there are increased levels of neutralizing antibodies in blood serum and in cervicovaginal mucosa, as well as higher production of specific B cells and T lymphocytes, which assures long-term memory and cross-protection against non-vaccine HPV strains. The vaccine is able to protect up to 93,2 % HPV-naive girls as compared with the control group, regardless of the nucleic acid of the virus type in the mucosa lesion. The safety profile of the vaccine is excellent.

• Klíčová slova
• karcinom děložního čípku, ASO4, MPL, adjuvantní prostředek, očkování,
• MeSH
• adjuvancia imunologická biosyntéza   klasifikace   MeSH
• dospělí MeSH
• imunizace MeSH
• klinické zkoušky jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidský papilomavirus 16 imunologie   MeSH
• lidský papilomavirus 18 imunologie   MeSH
• lipid A analogy a deriváty   MeSH
• mladý dospělý MeSH
• nádory děložního čípku prevence a kontrola   virologie   MeSH
• senioři MeSH
• tvorba protilátek imunologie   MeSH
• vakcíny proti papilomavirům * analýza   aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• virové vakcíny analýza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• přehledy MeSH

The present study was designed to assess whether a protective effect of the modified diphosphoryl lipid A (modLA) against myocardial ischemia-reperfusion injury (IRI) in rats can be related to the mechanism involving inducible nitric oxide synthase (iNOS). Pre-treatment with modLA significantly reduced the duration of both ventricular tachycardia (p < 0.01) and ventricular fibrillation (p < 0.001) compared to controls. Under these conditions the incidence of animal death was reduced (p < 0.05). The beneficial effect of modLA was markedly attenuated by the prior administration of selective iNOS inhibitor S-methylisothiourea (SMT). In this animal group, mortality was significantly increased (p < 0.01) partially in consequence of sustained ventricular arrhythmias. These results indicate that induction of iNOS can be responsible for cardioprotection of modLA.

• MeSH
• financování organizované MeSH
• inhibitory enzymů farmakologie   MeSH
• isothiuronium analogy a deriváty   farmakologie   MeSH
• kardiotonika farmakologie   MeSH
• krysa rodu rattus MeSH
• lipid A analogy a deriváty   farmakologie   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• potkani Wistar MeSH
• reperfuzní poškození myokardu patologie   prevence a kontrola   MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   MeSH
• tachykardie farmakoterapie   patofyziologie   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• antagonista receptoru pro interleukin 1 terapeutické užití   MeSH
• antikoagulancia terapeutické užití   MeSH
• experimentální terapie * MeSH
• interleukin-1 terapeutické užití   MeSH
• lidé MeSH
• lipid A škodlivé účinky   MeSH
• multiorgánové selhání farmakoterapie   MeSH
• oxid dusnatý antagonisté a inhibitory   škodlivé účinky   terapeutické užití   MeSH
• sepse * farmakoterapie   metabolismus   MeSH
• syndrom systémové zánětlivé reakce * farmakoterapie   patofyziologie   MeSH
• tumor nekrotizující faktory farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH