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1.
Vaccines (Basel) ; 12(7)2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39066452

RESUMEN

The most widely known pyrogen impurity in vaccines is the Gram-negative bacterial endotoxin lipopolysaccharide (LPS). When administered at toxic doses, endotoxin triggers inflammatory responses, which lead to endotoxic shock. The literature on endotoxic content (EC) for preclinical vaccines' formulations used in animal studies is very poor, and the recommended thresholds are solely based on commercial vaccine limits set for humans and are, therefore, not connected to the actual impact of EC on animal welfare for species used in preclinical research studies. An extensive study to evaluate the presence of a potential relationship between endotoxin content in formulations administered to mice (the most common species used in preclinical research studies) and their welfare was conducted to calculate an EC threshold for formulations of candidate vaccines. Three years of historical data, from more than 500 formulations of different antigen types (i.e., proteins, glycoconjugates, OMV/GMMA) injected into more than 5000 mice, was evaluated with two alternative statistical methodologies, both demonstrating that there is no significant relationship between actual endotoxin levels and mouse welfare. The calculation of thresholds was, therefore, performed by consistency versus formulations that demonstrated no impact on animal welfare.

2.
Sci Rep ; 8(1): 2593, 2018 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-29416049

RESUMEN

Group B Streptococcus (GBS) is a normal inhabitant of recto-vaginal mucosae in up to 30% of healthy women. Colonization is a major risk factor for perinatal infection which can lead to severe complications such as stillbirth and neonatal invasive disease. Intra-partum antibiotic prophylaxis in colonized women is a safe and cost-effective preventive measure against early-onset disease in the first days of life, but has no effect on late-onset manifestations or on early maternal infection. Maternal immunization with capsular polysaccharide-based vaccines shows promise for the prevention of both early-onset and late-onset neonatal infections, although ability to prevent maternal colonization and ascending infection has been less studied. Here we investigated the effect of a GBS glycoconjugate vaccine since the very early stage of maternal GBS acquisition to neonatal outcome by rodent models of vaginal colonization and ascending infection. Immunization of female mice and rats with a type III glycoconjugate reduced vaginal colonization, infection of chorioamniotic/ placental membranes and bacterial transmission to fetuses and pups. Type III specific antibodies were detected in the blood and vagina of vaccinated mothers and their offspring. The obtained data support a potential preventive effect of GBS glycoconjugate vaccines during the different stages of pregnancy.


Asunto(s)
Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Polisacáridos Bacterianos/inmunología , Infecciones Estreptocócicas/prevención & control , Vacunas Estreptocócicas/inmunología , Vagina/microbiología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Polisacáridos Bacterianos/administración & dosificación , Ratas , Infecciones Estreptocócicas/microbiología , Vacunas Estreptocócicas/administración & dosificación , Vacunación
3.
Sci Rep ; 6: 38043, 2016 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-27901071

RESUMEN

Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans. Characterization of the local and systemic inflammatory and immune responses following bacterial infection brought to light specific signatures of disease. Immunization of mice with the vaccine formulation we have recently described (4C-Staph), induced a strong antibody response and specific CD4+ effector memory T cells, and resulted in reduced bacterial load in the knee joints, a milder general inflammatory state and protection against bacterial-mediated cellular toxicity. Possible correlates of protection are finally proposed, which might contribute to the development of an effective vaccine for human use.


Asunto(s)
Artritis Infecciosa , Articulación de la Rodilla , Infecciones Estafilocócicas , Vacunas Estafilocócicas , Staphylococcus aureus/inmunología , Vacunación , Animales , Artritis Infecciosa/inmunología , Artritis Infecciosa/microbiología , Artritis Infecciosa/patología , Artritis Infecciosa/prevención & control , Femenino , Articulación de la Rodilla/inmunología , Articulación de la Rodilla/microbiología , Articulación de la Rodilla/patología , Ratones , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/patología , Infecciones Estafilocócicas/prevención & control , Vacunas Estafilocócicas/inmunología , Vacunas Estafilocócicas/farmacología
4.
PLoS One ; 11(8): e0161193, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27525409

RESUMEN

Current hemagglutinin (HA)-based seasonal influenza vaccines induce vaccine strain-specific neutralizing antibodies that usually fail to provide protection against mismatched circulating viruses. Inclusion in the vaccine of highly conserved internal proteins such as the nucleoprotein (NP) and the matrix protein 1 (M1) was shown previously to increase vaccine efficacy by eliciting cross-reactive T-cells. However, appropriate delivery systems are required for efficient priming of T-cell responses. In this study, we demonstrated that administration of novel self-amplifying mRNA (SAM®) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP-containing SAM also induced cytotoxic CD8 T cells. Robust expansions of central memory (TCM) and effector memory (TEM) CD4 and CD8 T cells were also measured. An enhanced recruitment of NP-specific cytotoxic CD8 T cells was observed in the lungs of SAM(NP)-immunized mice after influenza infection that paralleled with reduced lung viral titers and pathology, and increased survival after homologous and heterosubtypic influenza challenge. Finally, we demonstrated for the first time that the co-administration of RNA (SAM(M1-NP)) and protein (monovalent inactivated influenza vaccine (MIIV)) was feasible, induced simultaneously NP-, M1- and HA-specific T cells and HA-specific neutralizing antibodies, and enhanced MIIV efficacy against a heterologous challenge. In conclusion, systemic administration of SAM vectors expressing conserved internal influenza antigens induced protective immune responses in mice, supporting the SAM® platform as another promising strategy for the development of broad-spectrum universal influenza vaccines.


Asunto(s)
Antígenos Virales/genética , Antígenos Virales/inmunología , Secuencia Conservada , Virus de la Influenza A/inmunología , Virus de la Influenza A/fisiología , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Animales , Línea Celular , Cricetinae , Amplificación de Genes , Expresión Génica , Vectores Genéticos/genética , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H1N1 del Virus de la Influenza A/fisiología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/fisiología , Pulmón/inmunología , Ratones , ARN Mensajero/genética , Linfocitos T Citotóxicos/inmunología , Vacunas de Productos Inactivados/genética , Vacunas de Productos Inactivados/inmunología , Proteínas del Núcleo Viral/genética , Proteínas del Núcleo Viral/inmunología , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/inmunología
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