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1.
J Allergy Clin Immunol ; 152(5): 1107-1120.e6, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37595760

RESUMEN

BACKGROUND: Obesity and type 2 diabetes mellitus (T2DM) are associated with an increased risk of severe outcomes from infectious diseases, including coronavirus disease 2019. These conditions are also associated with distinct responses to immunization, including an impaired response to widely used severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines. OBJECTIVE: We sought to establish a connection between reduced immunization efficacy via modeling the effects of metabolic diseases on vaccine immunogenicity that is essential for the development of more effective vaccines for this distinct vulnerable population. METHODS: A murine model of diet-induced obesity and insulin resistance was used to model the effects of comorbid T2DM and obesity on vaccine immunogenicity and protection. RESULTS: Mice fed a high-fat diet (HFD) developed obesity, hyperinsulinemia, and glucose intolerance. Relative to mice fed a normal diet, HFD mice vaccinated with a SARS-CoV-2 mRNA vaccine exhibited significantly lower anti-spike IgG titers, predominantly in the IgG2c subclass, associated with a lower type 1 response, along with a 3.83-fold decrease in neutralizing titers. Furthermore, enhanced vaccine-induced spike-specific CD8+ T-cell activation and protection from lung infection against SARS-CoV-2 challenge were seen only in mice fed a normal diet but not in HFD mice. CONCLUSIONS: The study demonstrated impaired immunity following SARS-CoV-2 mRNA immunization in a murine model of comorbid T2DM and obesity, supporting the need for further research into the basis for impaired anti-SARS-CoV-2 immunity in T2DM and investigation of novel approaches to enhance vaccine immunogenicity among those with metabolic diseases.


Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Vacunas Virales , Animales , Humanos , Ratones , Vacunas contra la COVID-19 , SARS-CoV-2 , COVID-19/prevención & control , Modelos Animales de Enfermedad , Inmunogenicidad Vacunal , Dieta , Obesidad , ARN Mensajero , Anticuerpos Antivirales , Anticuerpos Neutralizantes
2.
J Immunol ; 206(6): 1240-1250, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33536255

RESUMEN

Intradermal vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) protects infants from disseminated tuberculosis, and i.v. BCG protects nonhuman primates (NHP) against pulmonary and extrapulmonary tuberculosis. In humans and NHP, protection is thought to be mediated by T cells, which typically recognize bacterial peptide Ags bound to MHC proteins. However, during vertebrate evolution, T cells acquired the capacity to recognize lipid Ags bound to CD1a, CD1b, and CD1c proteins expressed on APCs. It is unknown whether BCG induces T cell immunity to mycobacterial lipids and whether CD1-restricted T cells are resident in the lung. In this study, we developed and validated Macaca mulatta (Mamu) CD1b and CD1c tetramers to probe ex vivo phenotypes and functions of T cells specific for glucose monomycolate (GMM), an immunodominant mycobacterial lipid Ag. We discovered that CD1b and CD1c present GMM to T cells in both humans and NHP. We show that GMM-specific T cells are expanded in rhesus macaque blood 4 wk after i.v. BCG, which has been shown to protect NHP with near-sterilizing efficacy upon M. tuberculosis challenge. After vaccination, these T cells are detected at high frequency within bronchoalveolar fluid and express CD69 and CD103, markers associated with resident memory T cells. Thus, our data expand the repertoire of T cells known to be induced by whole cell mycobacterial vaccines, such as BCG, and show that lipid Ag-specific T cells are resident in the lungs, where they may contribute to protective immunity.


Asunto(s)
Antígenos Bacterianos/inmunología , Vacuna BCG/administración & dosificación , Glucolípidos/inmunología , Linfocitos T/inmunología , Tuberculosis/prevención & control , Adolescente , Animales , Antígenos Bacterianos/metabolismo , Antígenos CD1/metabolismo , Línea Celular , Niño , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Glicoproteínas/metabolismo , Voluntarios Sanos , Humanos , Inyecciones Intravenosas , Pulmón/citología , Pulmón/inmunología , Pulmón/microbiología , Macaca mulatta , Masculino , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología , Cultivo Primario de Células , Linfocitos T/metabolismo , Tuberculosis/sangre , Tuberculosis/inmunología , Tuberculosis/microbiología
3.
Nature ; 532(7597): 117-21, 2016 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-27027293

RESUMEN

Colonic epithelial cells are covered by thick inner and outer mucus layers. The inner mucus layer is free of commensal microbiota, which contributes to the maintenance of gut homeostasis. In the small intestine, molecules critical for prevention of bacterial invasion into epithelia such as Paneth-cell-derived anti-microbial peptides and regenerating islet-derived 3 (RegIII) family proteins have been identified. Although there are mucus layers providing physical barriers against the large number of microbiota present in the large intestine, the mechanisms that separate bacteria and colonic epithelia are not fully elucidated. Here we show that Ly6/PLAUR domain containing 8 (Lypd8) protein prevents flagellated microbiota invading the colonic epithelia in mice. Lypd8, selectively expressed in epithelial cells at the uppermost layer of the large intestinal gland, was secreted into the lumen and bound flagellated bacteria including Proteus mirabilis. In the absence of Lypd8, bacteria were present in the inner mucus layer and many flagellated bacteria invaded epithelia. Lypd8(-/-) mice were highly sensitive to intestinal inflammation induced by dextran sulfate sodium (DSS). Antibiotic elimination of Gram-negative flagellated bacteria restored the bacterial-free state of the inner mucus layer and ameliorated DSS-induced intestinal inflammation in Lypd8(-/-) mice. Lypd8 bound to flagella and suppressed motility of flagellated bacteria. Thus, Lypd8 mediates segregation of intestinal bacteria and epithelial cells in the colon to preserve intestinal homeostasis.


Asunto(s)
Colon/microbiología , Epitelio/microbiología , Flagelos , Proteínas Ligadas a GPI/metabolismo , Bacterias Gramnegativas/fisiología , Mucosa Intestinal/microbiología , Animales , Adhesión Bacteriana , Células CACO-2 , Línea Celular , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/genética , Sulfato de Dextran , Femenino , Proteínas Ligadas a GPI/deficiencia , Proteínas Ligadas a GPI/genética , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/metabolismo , Bacterias Gramnegativas/patogenicidad , Homeostasis , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/genética , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Masculino , Ratones , Proteus mirabilis/efectos de los fármacos , Proteus mirabilis/metabolismo , Proteus mirabilis/patogenicidad , Simbiosis
4.
Proc Natl Acad Sci U S A ; 115(33): 8418-8423, 2018 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-30061415

RESUMEN

The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CX3CR1high Mϕs. Intestinal CX3CR1high Mϕs highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spicflox/flox ) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CX3CR1high Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the noninflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.


Asunto(s)
Colitis/tratamiento farmacológico , Hemo/farmacología , Intestinos/inmunología , Macrófagos/inmunología , Animales , Receptor 1 de Quimiocinas CX3C/fisiología , Citocinas/biosíntesis , Proteínas de Unión al ADN/fisiología , Sulfato de Dextran/toxicidad , Hierro de la Dieta/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Receptores Toll-Like/fisiología , Factor de Transcripción ReIA/fisiología
5.
Int Immunol ; 28(11): 533-545, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27421871

RESUMEN

Inappropriate activation of T helper (Th) cells, such as Th1 and Th17 cells, is implicated in the pathogenesis of chronic inflammatory disorders including ulcerative colitis (UC). CX3CR1high macrophages contribute to intestinal homeostasis through various mechanisms in mice. However, whether mononuclear phagocytes with regulatory functions are present in the human colon is not clearly defined. We investigated whether innate myeloid cells that suppress activation of effector T cells exist in the human intestinal mucosa. Among intestinal lamina propria cells, Lin- HLA-DRhigh CD14+ CD163high cells were subdivided into CD160low and CD160high cells. Both subsets produced high levels of IL-10. CD163high CD160high cells suppressed effector T cell proliferation, whereas CD163high CD160low cells induced Th17 differentiation. Patients with UC exhibited increased numbers of CD163high CD160low cells, while showing profoundly decreased numbers of CD163high CD160high cells. In this context, CD163high CD160high cells had higher CD80/CD86 expression and lower IL10RB expression, and these cells did not suppress effector T cell proliferation. The CD163high CD160high subset in normal intestinal mucosa inhibits inappropriate Th1/Th17 responses through suppression of their proliferation, and its number and suppressive activity are impaired in patients with UC. These findings indicate how human innate immune cells might prevent UC development.


Asunto(s)
Homeostasis , Mucosa Intestinal/inmunología , Intestinos/citología , Intestinos/inmunología , Células Mieloides/inmunología , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/inmunología , Proliferación Celular , Proteínas Ligadas a GPI/inmunología , Humanos , Receptores de Superficie Celular/inmunología , Receptores Inmunológicos/inmunología , Células TH1/inmunología , Células Th17/inmunología
6.
Gastroenterology ; 145(6): 1380-91.e1, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23993972

RESUMEN

BACKGROUND & AIMS: Abnormal activity of innate immune cells and T-helper (Th) 17 cells has been implicated in the pathogenesis of autoimmune and inflammatory diseases, including Crohn's disease (CD). Intestinal innate immune (myeloid) cells have been found to induce development of Th17 cells in mice, but it is not clear if this occurs in humans or in patients with CD. We investigated whether human intestinal lamina propria cells (LPCs) induce development of Th17 cells and whether these have a role in the pathogenesis of CD. METHODS: Normal intestinal mucosa samples were collected from patients with colorectal cancer and noninflamed and inflamed regions of mucosa were collected from patients with CD. LPCs were isolated by enzymatic digestion and analyzed for expression of HLA-DR, lineage markers CD14 and CD163 using flow cytometry. RESULTS: Among HLA-DR(high) Lin(-) cells, we identified a subset of CD14(+) CD163(low) cells in intestinal LPCs; this subset expressed Toll-like receptor (TLR) 2, TLR4, and TLR5 mRNAs and produced interleukin (IL)-6, IL-1ß, and tumor necrosis factor in response to lipopolysaccharide. In vitro co-culture with naïve T cells revealed that CD14(+) CD163(low) cells induced development of Th17 cells. CD14(+) CD163(low) cells from inflamed regions of mucosa of patients with CD expressed high levels of IL-6, IL-23p19, and tumor necrosis factor mRNAs, and strongly induced Th17 cells. CD14(+) CD163(low) cells from the noninflamed mucosa of patients with CD also had increased abilities to induce Th17 cells compared with those from normal intestinal mucosa. CONCLUSIONS: CD14(+) CD163(low) cells in intestinal LPCs from normal intestinal mucosa induce differentiation of naive T cells into Th17 cells; this activity is increased in mucosal samples from patients with CD. These findings show how intestinal myeloid cell types could contribute to pathogenesis of CD and possibly other Th17-associated diseases.


Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Colon/patología , Enfermedad de Crohn/patología , Receptores de Lipopolisacáridos/metabolismo , Membrana Mucosa/patología , Células Mieloides/patología , Receptores de Superficie Celular/metabolismo , Células Th17/patología , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Colon/metabolismo , Enfermedad de Crohn/metabolismo , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Membrana Mucosa/metabolismo , Células Mieloides/inmunología , Fenotipo , Factor de Necrosis Tumoral alfa/metabolismo
7.
Microbiol Immunol ; 58(8): 463-6, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24909404

RESUMEN

The short- and long-term passive protective efficacy of a mixture of heat-killed cells of six serogroups/serotypes of Shigella strains (Shigella dysenteriae 1, S. flexneri 2a, S. flexneri 3a, S. flexneri 6, S. boydii 4, and S. sonnei) were studied in neonatal mice. Neonatal mice from immunized dams exhibited significant short- and long-term passive protection against individual challenge by each of the six Shigella strains. High IgG and IgA titers against the lipopolysaccharide from each of the six Shigella strains were observed in sera from immunized dams.


Asunto(s)
Disentería Bacilar/inmunología , Inmunidad Materno-Adquirida , Vacunas contra la Shigella/inmunología , Shigella/inmunología , Animales , Animales Recién Nacidos/inmunología , Anticuerpos Antibacterianos/inmunología , Disentería Bacilar/microbiología , Disentería Bacilar/prevención & control , Femenino , Humanos , Masculino , Ratones , Serogrupo , Shigella/química , Shigella/clasificación , Shigella/genética , Vacunas contra la Shigella/administración & dosificación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/inmunología
8.
Commun Biol ; 7(1): 709, 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38851856

RESUMEN

Vaccination reduces morbidity and mortality due to infections, but efficacy may be limited due to distinct immunogenicity at the extremes of age. This raises the possibility of employing adjuvants to enhance immunogenicity and protection. Early IFNγ production is a hallmark of effective vaccine immunogenicity in adults serving as a biomarker that may predict effective adjuvanticity. We utilized mass cytometry (CyTOF) to dissect the source of adjuvant-induced cytokine production in human blood mononuclear cells (BMCs) from newborns (~39-week-gestation), adults (~18-63 years old) and elders (>65 years of age) after stimulation with pattern recognition receptors agonist (PRRa) adjuvants. Dimensionality reduction analysis of CyTOF data mapped the BMC compartment, elucidated age-specific immune responses and profiled PRR-mediated activation of monocytes and DCs upon adjuvant stimulation. Furthermore, we demonstrated PRRa adjuvants mediated innate IFNγ induction and mapped NK cells as the key source of TLR7/8 agonist (TLR7/8a) specific innate IFNγ responses. Hierarchical clustering analysis revealed age and TLR7/8a-specific accumulation of innate IFNγ producing γδ T cells. Our study demonstrates the application of mass cytometry and cutting-edge computational approaches to characterize immune responses across immunologically distinct age groups and may inform identification of the bespoke adjuvantation systems tailored to enhance immunity in distinct vulnerable populations.


Asunto(s)
Adyuvantes Inmunológicos , Leucocitos Mononucleares , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Adulto , Persona de Mediana Edad , Adyuvantes Inmunológicos/farmacología , Anciano , Adulto Joven , Adolescente , Interferón gamma/metabolismo , Recién Nacido , Femenino , Masculino , Factores de Edad , Inmunidad Innata
9.
Sci Transl Med ; 16(757): eadm8451, 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39047117

RESUMEN

Messenger RNA (mRNA) vaccines were pivotal in reducing severe acute respiratory syndrome 2 (SARS-CoV-2) infection burden, yet they have not demonstrated robust durability, especially in older adults. Here, we describe a molecular adjuvant comprising a lipid nanoparticle (LNP)-encapsulated mRNA encoding interleukin-12p70 (IL-12p70). The bioactive adjuvant was engineered with a multiorgan protection (MOP) sequence to restrict transcript expression to the intramuscular injection site. Admixing IL-12-MOP (CTX-1796) with the BNT162b2 SARS-CoV-2 vaccine increased spike protein-specific immune responses in mice. Specifically, the benefits of IL-12-MOP adjuvantation included amplified humoral and cellular immunity and increased immune durability for 1 year after vaccination in mice. An additional benefit included the restoration of immunity in aged mice to amounts comparable to those achieved in young adult animals, alongside amplification with a single immunization. Associated enhanced dendritic cell and germinal center responses were observed. Together, these data demonstrate that an LNP-encapsulated IL-12-MOP mRNA-encoded adjuvant can amplify immunogenicity independent of age, demonstrating translational potential to benefit vulnerable populations.


Asunto(s)
Adyuvantes Inmunológicos , Vacunas contra la COVID-19 , Interleucina-12 , ARN Mensajero , SARS-CoV-2 , Vacunas de ARNm , Animales , Interleucina-12/metabolismo , SARS-CoV-2/inmunología , ARN Mensajero/metabolismo , ARN Mensajero/genética , Vacunas contra la COVID-19/inmunología , Ratones , Nanopartículas/química , Femenino , COVID-19/prevención & control , COVID-19/inmunología , Vacuna BNT162 , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Ratones Endogámicos C57BL , Adyuvantes de Vacunas , Humanos , Lípidos/química , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Inmunidad Celular , Inmunidad Humoral , Liposomas
10.
Sci Adv ; 10(27): eadg3747, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38959314

RESUMEN

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.


Asunto(s)
Adyuvantes Inmunológicos , Pirimidinas , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Humanos , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/metabolismo , Animales , Ratones , Adyuvantes Inmunológicos/farmacología , Receptor Toll-Like 7/agonistas , Pirimidinas/farmacología , Pirimidinas/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Imidazoles/farmacología , Imidazoles/química , Células THP-1 , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , COVID-19/virología , COVID-19/inmunología , FN-kappa B/metabolismo , Femenino , Descubrimiento de Drogas/métodos , Inmunidad Innata/efectos de los fármacos
11.
Microbiol Immunol ; 57(11): 762-71, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24033533

RESUMEN

The protective efficacy of and immune response to heat-killed cells of monovalent and hexavalent mixtures of six serogroups/serotypes of Shigella strains (Shigella dysenteriae 1, Shigella flexneri 2a, S. flexneri 3a, S. flexneri 6, Shigella boydii 4, and Shigella sonnei) were examined in a guinea pig colitis model. A monovalent or hexavalent mixture containing 1 × 10(7) of each serogroup/serotype of heat-killed Shigella cells was administered orally on Days 0, 7, 14 and 21. On Day 28, the immunized animals were challenged rectally with 1 × 10(9) live virulent cells of each of the six Shigella serogroups/serotypes. In all immunized groups, significant levels of protection were observed after these challenges. The serum titers of IgG and IgA against the lipopolysaccharide of each of the six Shigella serogroups/serotypes increased exponential during the course of immunization. High IgA titers against the lipopolysaccharide of each of the six Shigella serogroups/serotypes were also observed in intestinal lavage fluid from all immunized animals. These data indicate that a hexavalent mixture of heat-killed cells of the six Shigella serogroups/serotypes studied would be a possible broad-spectrum candidate vaccine against shigellosis.


Asunto(s)
Colitis/inmunología , Colitis/prevención & control , Disentería Bacilar/inmunología , Disentería Bacilar/prevención & control , Vacunas contra la Shigella/inmunología , Shigella/inmunología , Animales , Anticuerpos Antibacterianos/inmunología , Colitis/microbiología , Modelos Animales de Enfermedad , Disentería Bacilar/microbiología , Femenino , Cobayas , Humanos , Inmunización , Masculino , Shigella/química , Shigella/clasificación , Vacunas contra la Shigella/administración & dosificación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/inmunología
12.
NPJ Vaccines ; 8(1): 18, 2023 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-36788219

RESUMEN

Development of SARS-CoV-2 vaccines that protect vulnerable populations is a public health priority. Here, we took a systematic and iterative approach by testing several adjuvants and SARS-CoV-2 antigens to identify a combination that elicits antibodies and protection in young and aged mice. While demonstrating superior immunogenicity to soluble receptor-binding domain (RBD), RBD displayed as a protein nanoparticle (RBD-NP) generated limited antibody responses. Comparison of multiple adjuvants including AddaVax, AddaS03, and AS01B in young and aged mice demonstrated that an oil-in-water emulsion containing carbohydrate fatty acid monosulphate derivative (CMS:O/W) most effectively enhanced RBD-NP-induced cross-neutralizing antibodies and protection across age groups. CMS:O/W enhanced antigen retention in the draining lymph node, induced injection site, and lymph node cytokines, with CMS inducing MyD88-dependent Th1 cytokine polarization. Furthermore, CMS and O/W synergistically induced chemokine production from human PBMCs. Overall, CMS:O/W adjuvant may enhance immunogenicity and protection of vulnerable populations against SARS-CoV-2 and other infectious pathogens.

13.
bioRxiv ; 2022 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-36523401

RESUMEN

Background: Obesity and Type 2 Diabetes Mellitus (T2DM) are associated with an increased risk of severe outcomes from infectious diseases, including COVID-19. These conditions are also associated with distinct responses to immunization, including an impaired response to widely used SARS-CoV-2 mRNA vaccines. Objective: To establish a connection between reduced immunization efficacy via modeling the effects of metabolic diseases on vaccine immunogenicity that is essential for the development of more effective vaccines for this distinct vulnerable population. Methods: We utilized a murine model of diet-induced obesity and insulin resistance to model the effects of comorbid T2DM and obesity on vaccine immunogenicity and protection. Results: Mice fed a high-fat diet (HFD) developed obesity, hyperinsulinemia, and glucose intolerance. Relative to mice fed a normal diet (ND), HFD mice vaccinated with a SARS-CoV-2 mRNA vaccine exhibited significantly lower anti-spike IgG titers, predominantly in the IgG2c subclass, associated with a lower type 1 response, along with a 3.83-fold decrease in neutralizing titers. Furthermore, enhanced vaccine-induced spike-specific CD8 + T cell activation and protection from lung infection against SARS-CoV-2 challenge were seen only in ND mice but not in HFD mice. Conclusion: We demonstrate impaired immunity following SARS-CoV-2 mRNA immunization in a murine model of comorbid T2DM and obesity, supporting the need for further research into the basis for impaired anti-SARS-CoV-2 immunity in T2DM and investigation of novel approaches to enhance vaccine immunogenicity among those with metabolic diseases. Capsule summary: Obesity and type 2 diabetes impair SARS-CoV-2 mRNA vaccine efficacy in a murine model.

14.
ACS Chem Biol ; 17(9): 2559-2571, 2022 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-36028220

RESUMEN

Adjuvanted nanocarrier-based vaccines hold substantial potential for applications in novel early-life immunization strategies. Here, via mouse and human age-specific in vitro modeling, we identified the combination of a small-molecule STING agonist (2'3'-cyclic GMP-AMP, cGAMP) and a TLR7/8 agonist (CL075) to drive the synergistic activation of neonatal dendritic cells and precision CD4 T-helper (Th) cell expansion via the IL-12/IFNγ axis. We further demonstrate that the vaccination of neonatal mice with quadrivalent influenza recombinant hemagglutinin (rHA) and an admixture of two polymersome (PS) nanocarriers separately encapsulating cGAMP (cGAMP-PS) and CL075 (CL075-PS) drove robust Th1 bias, high frequency of T follicular helper (TFH) cells, and germinal center (GC) B cells along with the IgG2c-skewed humoral response in vivo. Dual-loaded cGAMP/CL075-PSs did not outperform admixed cGAMP-PS and CL075-PS in vivo. These data validate an optimally designed adjuvantation system via age-selected small-molecule synergy and a multicomponent nanocarrier formulation as an effective approach to induce type 1 immune responses in early life.


Asunto(s)
Hemaglutininas , Receptor Toll-Like 7 , Adyuvantes Inmunológicos/farmacología , Animales , Humanos , Inmunización , Interleucina-12 , Ratones , Vacunación
15.
Sci Rep ; 12(1): 16860, 2022 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-36258023

RESUMEN

Infection is the most common cause of mortality early in life, yet the broad potential of immunization is not fully realized in this vulnerable population. Most vaccines are administered during infancy and childhood, but in some cases the full benefit of vaccination is not realized in-part. New adjuvants are cardinal to further optimize current immunization approaches for early life. However, only a few classes of adjuvants are presently incorporated in vaccines approved for human use. Recent advances in the discovery and delivery of Toll-like receptor (TLR) agonist adjuvants have provided a new toolbox for vaccinologists. Prominent among these candidate adjuvants are synthetic small molecule TLR7/8 agonists. The development of an effective infant Bordetella pertussis vaccine is urgently required because of the resurgence of pertussis in many countries, contemporaneous to the switch from whole cell to acellular vaccines. In this context, TLR7/8 adjuvant based vaccine formulation strategies may be a promising tool to enhance and accelerate early life immunity by acellular B. pertussis vaccines. In the present study, we optimized (a) the formulation delivery system, (b) structure, and (c) immunologic activity of novel small molecule imidazoquinoline TLR7/8 adjuvants towards human infant leukocytes, including dendritic cells. Upon immunization of neonatal mice, this TLR7/8 adjuvant overcame neonatal hyporesponsiveness to acellular pertussis vaccination by driving a T helper (Th)1/Th17 biased T cell- and IgG2c-skewed humoral response to a licensed acellular vaccine (DTaP). This potent immunization strategy may represent a new paradigm for effective immunization against pertussis and other pathogens in early life.


Asunto(s)
Tos Ferina , Animales , Niño , Humanos , Lactante , Ratones , Adyuvantes Inmunológicos/farmacología , Adyuvantes Farmacéuticos , Vacuna contra la Tos Ferina , Receptor Toll-Like 7/agonistas , Vacunación , Vacunas Acelulares , Tos Ferina/epidemiología
16.
Commun Biol ; 5(1): 790, 2022 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-35933439

RESUMEN

The SARS-CoV-2 Omicron variant evades vaccine-induced immunity. While a booster dose of ancestral mRNA vaccines effectively elicits neutralizing antibodies against variants, its efficacy against Omicron in older adults, who are at the greatest risk of severe disease, is not fully elucidated. Here, we evaluate multiple longitudinal immunization regimens of mRNA BNT162b2 to assess the effects of a booster dose provided >8 months after the primary immunization series across the murine lifespan, including in aged 21-month-old mice. Boosting dramatically enhances humoral and cell-mediated responses with evidence of Omicron cross-recognition. Furthermore, while younger mice are protected without a booster dose, boosting provides sterilizing immunity against Omicron-induced lung infection in aged 21-month-old mice. Correlational analyses reveal that neutralizing activity against Omicron is strongly associated with protection. Overall, our findings indicate age-dependent vaccine efficacy and demonstrate the potential benefit of mRNA booster immunization to protect vulnerable older populations against SARS-CoV-2 variants.


Asunto(s)
COVID-19 , Vacunas Virales , Animales , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Humanos , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/genética , SARS-CoV-2 , Vacunación , Vacunas Virales/genética
17.
Res Sq ; 2022 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-36597547

RESUMEN

mRNA vaccines have been key to addressing the SARS-CoV-2 pandemic but have impaired immunogenicity and durability in vulnerable older populations. We evaluated the mRNA vaccine BNT162b2 in human in vitro whole blood assays with supernatants from adult (18-50 years) and elder (≥60 years) participants measured by mass spectrometry and proximity extension assay proteomics. BNT162b2 induced increased expression of soluble proteins in adult blood (e.g., C1S, PSMC6, CPN1), but demonstrated reduced proteins in elder blood (e.g., TPM4, APOF, APOC2, CPN1, and PI16), including 30-85% lower induction of TH1-polarizing cytokines and chemokines (e.g., IFNγ, and CXCL10). Elder TH1 impairment was validated in mice in vivo and associated with impaired humoral and cellular immunogenicity. Our study demonstrates the utility of a human in vitro platform to model age-specific mRNA vaccine activity, highlights impaired TH1 immunogenicity in older adults, and provides rationale for developing enhanced mRNA vaccines with greater immunogenicity in vulnerable populations.

18.
Sci Transl Med ; 14(629): eabj5305, 2022 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-34783582

RESUMEN

Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.


Asunto(s)
Hidróxido de Aluminio , COVID-19 , Anciano , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , Vacunas contra la COVID-19 , Humanos , Ratones , Pandemias , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunas Sintéticas , Vacunas de ARNm
19.
Microbiol Immunol ; 55(10): 683-93, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21806676

RESUMEN

A non-invasive live transconjugant Shigella hybrid (LTSHΔstx) strain was constructed from a Shiga toxin gene deleted mutant of Shigella dysenteriae 1 by introducing a plasmid vector pPR1347 that carried a lipopolysaccharide biosynthesis gene (rfb and rfc) of Salmonella typhimurium. In guinea pigs, four successive oral administrations of LTSH Δstx showed complete protection against rectal challenge with wild type S. dysenteriae 1 strain. Exponential increase of the serum IgG and IgA titer against lipopolysaccharide of LTSH Δstx was observed during immunization, peaked on day 28 and remained at that level until day 35 after the initiation of the immunization. In intestinal lavage of the immunized animals, significant increase of IgA titer against lipopolysaccharide of LTSH Δstx was also observed. These data suggested that LTSH Δstx could be a useful candidate to induce protective immunity against S. dysenteriae 1 infection.


Asunto(s)
Disentería Bacilar/inmunología , Disentería Bacilar/prevención & control , Shigella dysenteriae/inmunología , Animales , Anticuerpos Antibacterianos/inmunología , Modelos Animales de Enfermedad , Disentería Bacilar/microbiología , Femenino , Cobayas , Humanos , Inmunización , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Lipopolisacáridos/inmunología , Masculino , Shigella dysenteriae/fisiología
20.
Front Immunol ; 12: 662218, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35222350

RESUMEN

Traditional vaccine development against infectious diseases has been guided by the overarching aim to generate efficacious vaccines normally indicated by an antibody and/or cellular response that correlates with protection. However, this approach has been shown to be only a partially effective measure, since vaccine- and pathogen-specific immunity may not perfectly overlap. Thus, some vaccine development strategies, normally focused on targeted generation of both antigen specific antibody and T cell responses, resulting in a long-lived heterogenous and stable pool of memory lymphocytes, may benefit from better mimicking the immune response of a natural infection. However, challenges to achieving this goal remain unattended, due to gaps in our understanding of human immunity and full elucidation of infectious pathogenesis. In this review, we describe recent advances in the development of effective vaccines, focusing on how understanding the differences in the immunizing and non-immunizing immune responses to natural infections and corresponding shifts in immune ontogeny are crucial to inform the next generation of infectious disease vaccines.


Asunto(s)
Señales (Psicología) , Vacunas , Humanos , Inmunidad Innata , Linfocitos T
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