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1.
Nature ; 594(7862): 253-258, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33873199

RESUMEN

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).


Asunto(s)
Adyuvantes Inmunológicos , Anticuerpos Neutralizantes/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas de Subunidad/inmunología , Compuestos de Alumbre , Animales , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , COVID-19/virología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Modelos Animales de Enfermedad , Inmunidad Celular , Inmunidad Humoral , Macaca mulatta/inmunología , Masculino , Oligodesoxirribonucleótidos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Escualeno
2.
bioRxiv ; 2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33594366

RESUMEN

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor-binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.

3.
Mol Ther ; 13(6): 1173-84, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16497561

RESUMEN

Congenital neurodegenerative diseases exhibit progressive postnatal neurologic impairment leading to premature death and are intractable to systemic therapies such as bone marrow transplantation. We injected bone marrow-derived mesenchymal stem cells (MSCs) into the CNS of young adult rhesus macaques to evaluate their safety and feasibility as vectors for direct intervention of neurologic disorders. Levels of engrafted male, donor MSCs were quantified in the CNS of female transplant recipients by real-time PCR using an SRY gene-specific probe. Analysis of coronal brain slices encompassing one-third of the total brain volume revealed engraftment levels ranging from 0.026 x 10(-3) to 0.163 x 10(-3)% of the total DNA content of brain tissue. Fine-mapping revealed male DNA distributed within specific anatomic structures along the neuraxis where label-retaining MSCs were visualized in histological sections by immunohistochemistry. Double labeling of sections confirmed that engrafted donor cells lacked expression of the macrophage marker CD68, the astrocytes marker GFAP, and neuronal markers NeuN and MAP2. MSC engraftment had no adverse effects on animal health, behavior, postural and locomotor patterns, or upper limb motor performance evaluated over a 6-month period posttransplantation. Therefore, MSC-based therapies represent a safe alternative for clinical intervention of CNS disorders.


Asunto(s)
Sistema Nervioso Central/fisiología , Trasplante de Células Madre/métodos , Factores de Edad , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígenos Nucleares/metabolismo , Conducta Animal/fisiología , Biomarcadores/metabolismo , Trasplante de Médula Ósea/métodos , Encéfalo/citología , Encéfalo/fisiología , Diferenciación Celular , Evaluación Preclínica de Medicamentos , Femenino , Macaca mulatta , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Actividad Motora , Proteínas del Tejido Nervioso/metabolismo , Reacción en Cadena de la Polimerasa , Proteína de la Región Y Determinante del Sexo/genética , Pruebas de Toxicidad
4.
Stem Cells ; 22(7): 1356-72, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15579653

RESUMEN

Expression of TERT, the catalytic protein subunit of the telomerase complex, can be used to generate cell lines that expand indefinitely and retain multilineage potential. We have created immortal adipose stromal cell lines (ATSCs) by stably transducing nonhuman primate-derived ATSCs with a retroviral vector expressing TERT. Transduced cells (ATSC-TERT) had an increased level of telomerase activity and increased mean telomere length in the absence of malignant cellular transformation. Long-term culture of the ATSC-TERT cells demonstrated that the cells retain the ability to undergo differentiation along multiple lineages such as adipogenic, chondrogenic, and neurogenic. Untransduced cells demonstrated markedly reduced multilineage and self-renewal potentials after 12 passages in vitro. To determine the functional role of telomerase during osteogenesis, we examined osteogenic differentiation potential of ATSC-TERT cells in vitro. Compared with naive ATSCs, which typically begin to accumulate calcium after 3-4 weeks of induction by osteogenic differentiation medium, ATSC-TERT cells were found to accumulate significant amounts of calcium after only 1 week of culture in osteogenic induction medium. The cells have increased production of osteoblastic markers, such as AP2, osteoblast-specific factor 2, chondroitin sulfate proteoglycan 4, and the tumor necrosis factor receptor superfamily, compared with control ATSCs, indicating that telomerase expression may aid in maintaining the osteogenic stem cell pool during in vitro expansion. These results show that ectopic expression of the telomerase gene in nonhuman primate ATSCs prevents senescence-associated impairment of osteoblast functions and that telomerase therapy may be a useful strategy for bone regeneration and repair.


Asunto(s)
Tejido Adiposo/metabolismo , Osteoblastos/citología , Células del Estroma/citología , Telomerasa/metabolismo , Animales , Antígenos/metabolismo , Calcio/metabolismo , Moléculas de Adhesión Celular/metabolismo , Diferenciación Celular , Línea Celular , Células Cultivadas , Condrocitos/citología , Medios de Cultivo/farmacología , ADN Complementario/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Inmunohistoquímica , Microscopía Fluorescente , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteoblastos/metabolismo , Primates , Estructura Terciaria de Proteína , Proteoglicanos/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Retroviridae/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Ingeniería de Tejidos , Factor de Transcripción AP-2 , Factores de Transcripción/metabolismo
5.
Science ; 306(5695): 485-7, 2004 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-15486300

RESUMEN

Topical agents, such as microbicides, that can protect against human immunodeficiency virus (HIV) transmission are urgently needed. Using a chimeric simian/human immunodeficiency virus (SHIV SF162), which is tropic for the chemokine receptor CCR5, we report that topical application of high doses of PSC-RANTES, an amino terminus-modified analog of the chemokine RANTES, provided potent protection against vaginal challenge in rhesus macaques. These experimental findings have potentially important implications for understanding vaginal transmission of HIV and the design of strategies for its prevention.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Antiinfecciosos Locales/uso terapéutico , Antagonistas de los Receptores CCR5 , Quimiocina CCL5/análogos & derivados , Quimiocina CCL5/uso terapéutico , Infecciones por VIH/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Vagina/virología , Administración Intravaginal , Animales , Fármacos Anti-VIH/administración & dosificación , Antiinfecciosos Locales/administración & dosificación , Anticuerpos Antivirales/sangre , Quimiocina CCL5/administración & dosificación , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Infecciones por VIH/transmisión , VIH-1/efectos de los fármacos , Macaca mulatta , Receptores CCR5/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/inmunología
6.
Virology ; 328(1): 19-29, 2004 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-15380354

RESUMEN

Human immunodeficiency virus type 1 (HIV-1) fusion with its target cells is initiated by sequential interactions between its envelope glycoprotein, CD4, and a co-receptor, usually CCR5 or CXCR4. Small molecules that bind to CCR5 and prevent its use by R5 HIV-1 strains are now being developed clinically as antiviral drugs. To test whether a block to CCR5 promotes the replication of viruses that enter cells via CXCR4 and are associated with accelerated disease progression, we administered a small molecule CCR5 inhibitor, CMPD 167, to three macaques dual-infected with both R5 (SIVmac251) and X4 (SHIV-89.6P) viruses. CMPD 167 caused a rapid and substantial (on average, 50-fold) suppression of R5 virus replication in each animal. In two of the animals, but not in the third, a rapid, transient, 8- to 15-fold increase in the amount of plasma X4 virus occurred. In neither animal was the increase in X4 viral load sustained throughout therapy, however. These observations may have relevance for the development of CCR5 inhibitors for treatment of HIV-1 infection of humans.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Antagonistas de los Receptores CCR5 , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Pirazoles/uso terapéutico , Virus Reordenados , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios , Valina/uso terapéutico , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Infecciones por VIH/virología , VIH-1/fisiología , Macaca mulatta , Virus Reordenados/fisiología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Valina/análogos & derivados , Carga Viral , Replicación Viral/efectos de los fármacos
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