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1.
Biologicals ; 84: 101721, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37922625

RESUMEN

The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) is reviewing World Health Organization (WHO) manuals, guidelines and recommendations for vaccines and biotherapeutics to identify the extent to which animal-based testing methods are described. The aim is to recommend where updates to these documents can lead to an increased and more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction and Refinement of animal tests) in the quality control and batch release testing requirements for vaccines and biotherapeutics. Improved adoption of 3Rs principles and non-animal testing strategies will help to reduce the delays and costs associated with product release testing. Developing recommendations that are widely applicable by both the manufacturers and national regulatory authorities for vaccines and biological therapeutics globally requires a detailed understanding of how different organisations view the opportunities and barriers to better integration of the 3Rs. To facilitate this, we developed and distributed a survey aimed at individuals who work for national regulatory authorities (NRAs) and/or national control laboratories (NCLs). In this paper, we present the key findings from this survey and how these will help inform the recommendations for wider integration of 3Rs approaches by WHO in their guidance documents applicable to the quality control and batch release testing of vaccines and biotherapeutics.


Asunto(s)
Laboratorios , Vacunas , Humanos , Animales , Factores Biológicos , Control de Calidad , Encuestas y Cuestionarios
2.
Lancet Glob Health ; 11(11): e1819-e1826, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37858591

RESUMEN

Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in low-income and middle-income countries (LMICs). Several Shigella vaccine candidates are advancing in clinical trials and offer promise. Although multiple target populations might benefit from a Shigella vaccine, the primary strategic goal of WHO is to accelerate the development and accessibility of safe, effective, and affordable Shigella vaccines that reduce mortality and morbidity in children younger than 5 years living in LMICs. WHO consulted with regulators and policy makers at national, regional, and global levels to evaluate pathways that could accelerate regulatory approval in this priority population. Special consideration was given to surrogate efficacy biomarkers, the role of controlled human infection models, and the establishment of correlates of protection. A field efficacy study in children younger than 5 years in LMICs is needed to ensure introduction in this priority population.


Asunto(s)
Disentería Bacilar , Vacunas contra la Shigella , Niño , Humanos , Países en Desarrollo , Disentería Bacilar/prevención & control , Disentería Bacilar/epidemiología
3.
Biologicals ; 81: 101660, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36376163

RESUMEN

The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) has been tasked by the World Health Organization (WHO) to review the extent to which animal-based testing methods are described in their manuals, guidelines and recommendations for vaccines and biotherapeutics. The aim is to identify and recommend where updates to these documents can lead to an increased and more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction and Refinement of animal tests) in the quality control and batch release testing requirements for vaccines and biotherapeutics. Developing recommendations that are widely applicable by both the manufacturers and national regulatory authorities for vaccines and biologicals globally requires a detailed understanding of how different organisations view the opportunities and barriers to better integration of the 3Rs. To facilitate this, we developed and distributed a survey aimed at vaccine and biotherapeutics manufacturers in July 2021. In this paper, we present the key findings from this survey and how these will help inform the recommendations for wider integration of 3Rs approaches by WHO in their guidance documents applicable to the quality control and batch testing of vaccines and biotherapeutics.


Asunto(s)
Vacunas , Animales , Factores Biológicos , Control de Calidad , Organización Mundial de la Salud
4.
Vaccine ; 40(32): 4283-4291, 2022 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-35779963

RESUMEN

Worldwide, childhood mortality has declined significantly, with improvements in hygiene and vaccinations against common childhood illnesses, yet newborn mortality remains high. Group B Streptococcus (GBS) disease significantly contributes to newborn mortality and is the leading cause of meningitis in infants. Many years of research have demonstrated the potential for maternal vaccination against GBS to confer protection to the infant, and at least three vaccine candidates are currently undergoing clinical trials. Given the relatively low disease incidence, any clinical vaccine efficacy study would need to include at least 40,000 to 60,000 participants. Therefore, a path to vaccine licensure based on a correlate of protection (CoP) would be the preferred route, with post-approval effectiveness studies demonstrating vaccine impact on reduction of disease burden likely to be required as part of conditional marketing approval. This workshop, hosted by the Bill & Melinda Gates Foundation on 10 and 11 February 2021, discussed considerations and potential statistical methodologies for establishing a CoP for GBS disease. Consensus was reached that an antibody marker with global threshold predictive of a high level of vaccine protection would be most beneficial for licensure assessments. IgG binding antibody in cord blood would likely serve as the CoP, with additional studies needed to confirm a high correlation with functional antibody and to demonstrate comparable kinetics of natural versus vaccine-induced antibody. Common analyses of ongoing seroepidemiological studies include estimation of absolute and relative disease risk as a function of infant antibody concentration, with adjustment for confounders of the impact of antibody concentration on infant GBS disease including gestational age and maternal age. Estimation of an antibody concentration threshold indicative of high protection should build in margin for uncertainties from sources including unmeasured confounders, imperfect causal mediation, and variability in point and confidence interval estimates across regions and/or serotypes.


Asunto(s)
Infecciones Estreptocócicas , Niño , Sangre Fetal , Humanos , Inmunoglobulina G , Lactante , Recién Nacido , Serogrupo , Infecciones Estreptocócicas/prevención & control , Streptococcus agalactiae , Vacunación
5.
Vaccines (Basel) ; 10(4)2022 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-35455238

RESUMEN

Vaccine candidates for Shigella are approaching phase 3 clinical trials in the target population of young children living in low- and middle-income countries. Key study design decisions will need to be made to maximize the success of such trials and minimize the time to licensure and implementation. We convened an ad hoc working group to identify the key aspects of trial design that would meet the regulatory requirements to achieve the desired indication of prevention of moderate or severe shigellosis due to strains included in the vaccine. The proposed primary endpoint of pivotal Shigella vaccine trials is the efficacy of the vaccine against the first episode of acute moderate or severe diarrhea caused by the Shigella strains contained within the vaccine. Moderate or severe shigellosis could be defined by a modified Vesikari score with dysentery and molecular detection of vaccine-preventable Shigella strains. This report summarizes the rationale and current data behind these considerations, which will evolve as new data become available and after further review and consultation by global regulators and policymakers.

6.
Biologicals ; 74: 24-27, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34750045

RESUMEN

Animal testing has long been integral to the development of biologicals, including vaccines. The use of animals can provide important information on potential toxicity, insights into their mechanism of action, pharmacokinetics and dynamics, physiologic distribution, and potency. However, the use of these same methods is often adopted into the post-licensure phase of the product life cycle for the monitoring of product qualities, such as potency or safety, as part of their routine batch release. The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) and the World Health Organization (WHO) are collaborating on a project to review animal-based testing methods described in WHO manuals, guidelines and recommendations for biologicals to identify where updates can lead to a more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction, and Refinement of animal tests) in batch release testing requirements. An international working group consisting of more than 30 representatives from pharmaceutical and biotechnology companies, national control laboratories and regulatory bodies is performing this review. This project aims to address concerns about inconsistencies in the guidance for the scientifically justified use of animal methods required for the post-licensure quality control and batch release testing of biologicals, and the near absence of recommendations for the application of 3Rs principles within the relevant guidelines. Improved adoption of 3Rs principles and non-animal testing strategies will help to reduce the delays and costs associated with product release testing and help support faster access to products by the global communities who need them most urgently.


Asunto(s)
Productos Biológicos , Control de Calidad , Vacunas , Alternativas a las Pruebas en Animales , Animales , Productos Biológicos/normas , Vacunas/normas , Organización Mundial de la Salud
7.
Biologicals ; 42(4): 199-204, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24882365

RESUMEN

Tetanus vaccines contain detoxified tetanus neurotoxin. In order to check for residual toxicity, the detoxified material (toxoid) has to be tested in guinea pigs. These tests are time-consuming and raise animal welfare issues. In line with the "3R" principles of replacing, reducing and refining animal tests, the "binding and cleavage" (BINACLE) assay for detection of active tetanus neurotoxin has been developed as a potential alternative to toxicity testing in animals. This in vitro test system can discriminate well between toxic and detoxified toxin molecules based on their receptor-binding and proteolytic characteristics. Here we describe an international study to assess the transferability of the BINACLE assay. We show that all participating laboratories were able to successfully perform the assay. Generally, assay variability was within an acceptable range. A toxin concentration-dependent increase of assay signals was observed in all tests. Furthermore, participants were able to detect low tetanus neurotoxin concentrations close to the estimated in vivo detection limit. In conclusion, the data from this study indicate that the methodology of the BINACLE assay seems to be robust, reproducible and easily transferable between laboratories. These findings substantiate our notion that the method can be suitable for the routine testing of tetanus toxoids.


Asunto(s)
Proteolisis , Toxoide Tetánico/toxicidad , Pruebas de Toxicidad/normas , Animales , Estudios de Factibilidad , Cobayas , Internacionalidad , Ensayos de Aptitud de Laboratorios , Límite de Detección , Unión Proteica , Reproducibilidad de los Resultados , Transferencia de Tecnología , Toxina Tetánica/aislamiento & purificación , Toxina Tetánica/metabolismo , Toxoide Tetánico/metabolismo , Toxoide Tetánico/normas , Pruebas de Toxicidad/métodos
8.
Biologicals ; 42(2): 114-22, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24394373

RESUMEN

Regulatory authorities require safety and potency testing prior to the release of each production lot of acellular pertussis (aP)-containing vaccines. Currently, the murine histamine sensitization test (HIST) is used to evaluate the presence of residual pertussis toxin in aP containing vaccines. However, the testing requires the use of a significant number of mice and results in unrelieved pain and distress. NICEATM, ICCVAM, their partners in the International Cooperation on Alternative Test Methods, and the International Working Group for Alternatives to HIST organized a workshop to discuss recent developments in alternative assays to the HIST, review data from an international collaborative study on non-animal alternative tests that might replace the HIST, and address the path toward global acceptance of this type of method. Currently, there are three potential alternative methods to HIST. Participants agreed that no single in vitro method was sufficiently developed for harmonized validation studies at this time. It is unlikely that any single in vitro method would be applicable to all aP vaccines without modification, due to differences between vaccines. Workshop participants recommended further optimization of cell-based assays under development. Participants agreed that the next international collaborative studies should commence in 2013 based on discussions during this workshop.


Asunto(s)
Histamina/inmunología , Vacuna contra la Tos Ferina/inmunología , Vacunas Acelulares/inmunología , Animales , Internacionalidad , Ratones
10.
Procedia Vaccinol ; 5: 16-32, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-32288913

RESUMEN

NICEATM and ICCVAM convened an international workshop to review the state of the science of human and veterinary vaccine potency and safety testing methods, and to identify opportunities to advance new and improved methods that can further reduce, refine, and replace animal use. This report addresses methods and strategies identified by workshop participants for replacement of animals used for potency testing of human vaccines. Vaccines considered to have the highest priority for future efforts were (1) vaccines for which antigen quantification methods are already developed but not validated, (2) vaccines/components that require the largest number of animals, (3) vaccines that require an in vivo challenge test, and (4) vaccines with in vivo tests that are highly variable and cause a significant number of invalid tests. Vaccine potency tests identified as the highest priorities for replacement were those for diphtheria and tetanus, pertussis (whole cell and acellular), rabies, anthrax, polio vaccine (inactivated) and complex combination vaccines based on DT or DTwP/aP. Research into understanding the precise mechanism of protection afforded by vaccines and the identification of clinically relevant immunological markers are needed to facilitate the successful implementation of in vitro testing alternatives. This report also identifies several priority human vaccines and associated research objectives that are necessary to successfully implement in vitro vaccine potency testing alternatives.

11.
Vaccine ; 28(15): 2687-92, 2010 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-20123053

RESUMEN

A binding assay was recently published that differentiates between pertussis toxin (PTx) and the pertussis toxoid (PTd) used in acellular pertussis vaccines based on the selective binding of PTx to fetuin and detection with a polyclonal antibody. We found that the assay specificity for PTx was affected by both pH and salt. A monoclonal antibody (mAb) was identified that eliminated specificity problems and improved the sensitivity to 0.4 ngPTx/ml. This mAb was previously shown to neutralize PTx toxicity in vivo, thereby supporting the assay's potential biological relevance as an alternative to the mouse histamine sensitivity test for the safety of pertussis vaccines.


Asunto(s)
Técnicas de Química Analítica/métodos , Toxina del Pertussis/análisis , Vacunas/química , Anticuerpos Monoclonales/metabolismo , Antitoxinas/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Inmunoensayo/métodos , Concentración Osmolar , Unión Proteica , Sensibilidad y Especificidad , alfa-Fetoproteínas/metabolismo
12.
J Chromatogr A ; 1217(19): 3297-306, 2010 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-19931086

RESUMEN

Interferon alpha-2 (IFN alpha-2) products have been widely used as antivirals for the treatment of serious diseases such as hepatitis B and C. However, reports of adverse reactions following treatment have prompted investigations into the cause of these undesirable events. In this study size-exclusion HPLC (SE-HPLC) methods coupled with intrinsic fluorescence detection were developed for evaluating the stability and degradation profiles of IFN alpha-2 drug substances and drug products. The method allowed baseline resolution of the active ingredient from the excipients present in the finished products that included large amounts of albumin. Limits of detection (S/N>or=3) for IFN alpha-2a and IFN alpha-2b were 32 ng/mL and 28 ng/mL, respectively and good repeatability of chromatographic profiles (%RSD<2.1) was obtained. High molecular weight (HMW) aggregates with apparent molecular weight of approximately 650 kDa as well as dimers, denatured and reduced variants were successfully identified and separated from native IFN alpha-2 proteins. This chromatographic method, which quantitatively measures physical and chemical changes taking place in solution formulations, was found to be capable of monitoring IFN alpha-2a and IFN alpha-2b stability. Potency assay results revealed up to 87% decrease in biological activity of the physically and chemically altered variants compared to the original IFNs.


Asunto(s)
Cromatografía en Gel/métodos , Cromatografía Líquida de Alta Presión/métodos , Interferón Tipo I/química , Muerte Celular/efectos de los fármacos , Células Hep G2 , Humanos , Interferón Tipo I/metabolismo , Interferón Tipo I/farmacología , Modelos Lineales , Conformación Proteica , Desnaturalización Proteica , Multimerización de Proteína , Estabilidad Proteica , Proteínas Recombinantes , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Fluorescencia , Temperatura
13.
J Pharmacol Exp Ther ; 331(2): 733-9, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19692635

RESUMEN

Lasonolide A, a novel polyketide-derived macrolide, was previously identified from an extract of the marine sponge Forcepia sp. in an assay for protein kinase C (PKC) inhibitors. Cytotoxicity testing and profiling of lasonolide A in the National Cancer Institute (NCI) 60 cell panel screen revealed that it was potent toward a broad range of cell lines and also suggested a unique mechanism of action. Contrary to expected results, we found lasonolide A to be a strong activator of PKC in Panc-1 pancreatic carcinoma cells. Downstream mitogen-activated protein kinases, ERK 1/2 and p38 were also rapidly phosphorylated in response to lasonolide A, as was Akt. Microscopy studies revealed that lasonolide A induced blebbing and contraction of the cells within minutes of exposure, and the eventual loss of adherence. However, membrane integrity was maintained and the effects were reversible if lasonolide A was washed from the cells after their loss of adherence. Pretreatment of cells with a myosin II inhibitor, blebbistatin, slowed the early onset, but did not prevent the morphological effects of lasonolide A. Cells stained for actin filaments showed some reduction in stress fiber structure after lasonolide A exposure; however, it did not affect the polymerization of purified actin in vitro. Bisindolemaleimide, a PKC inhibitor, and wortmannin, a phosphoinositide 3-kinase; inhibitor, did not reduce lasonolide A-induced contraction or blebbing or the activation of mitogen-activated protein kinases, although Akt phosphorylation was prevented by wortmannin pretreatment. Our results indicate that lasonolide A activates multiple signal transduction pathways and suggest that the origin is upstream of PKC.


Asunto(s)
Macrólidos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Actinas/metabolismo , Animales , Western Blotting , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/ultraestructura , Supervivencia Celular/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , L-Lactato Deshidrogenasa/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neoplasias Pancreáticas/patología , Fosforilación , Poríferos/química , Proteína Quinasa C/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Sales de Tetrazolio , Tiazoles , Tubulina (Proteína)/metabolismo
14.
J Nat Prod ; 67(1): 110-1, 2004 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-14738400

RESUMEN

Plakolide A (1), a new alpha-exomethylene-gamma-lactone isolated from the marine sponge Plakortis sp., was found to inhibit inducible nitric oxide synthase (iNOS) activity. The isolation, structure elucidation, and biological activity of plakolide A is described.


Asunto(s)
Inhibidores Enzimáticos/aislamiento & purificación , Lactonas/aislamiento & purificación , Óxido Nítrico Sintasa/antagonistas & inhibidores , Poríferos/química , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Lactonas/química , Lactonas/farmacología , Estructura Molecular , Óxido Nítrico Sintasa de Tipo II
15.
Biochem Pharmacol ; 66(1): 75-82, 2003 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-12818367

RESUMEN

Dictyostatin-1 had previously been isolated from a marine sponge of the genus Spongia sp. and described as a cytotoxic agent to murine and human cancer cells, but its mechanism of activity was unknown. In a routine screening assay used to detect cytotoxic compounds of marine origin, dictyostatin-1 was identified as a highly active component in an extract from a Lithistida sponge and exploration into its pharmacology was pursued. Initial studies demonstrated that dictyostatin-1 arrested cells in the G(2)/M phase of the cell cycle. Staining of these cells with antitubulin revealed cells having multiple aster formations and microtubule matrix bundling patterns similar to that seen in cells exposed to paclitaxel. Dictyostatin-1 was able to induce the polymerization of purified bovine brain tubulin in vitro and the polymerized tubulin remained stable at cold temperatures. Dictyostatin-1 also proved to be highly potent in two paclitaxel-resistant human cancer cell lines expressing active P-glycoprotein. Together, these results indicate that dictyostatin-1 is a potent inducer of tubulin polymerization and retains activity in cells expressing the P-glycoprotein efflux pump.


Asunto(s)
Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Lactonas/farmacología , Macrólidos , Microtúbulos/efectos de los fármacos , Poríferos/química , Tubulina (Proteína)/metabolismo , Animales , Biopolímeros/metabolismo , División Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Humanos , Lactonas/química , Biología Marina , Células Tumorales Cultivadas
16.
J Nat Prod ; 65(12): 1830-7, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12502323

RESUMEN

A series of 12 semisynthetic discodermolide analogues, 2-13, have been prepared using natural (+)-discodermolide (1) and evaluated for in vitro cytotoxicity against cultured murine P-388 leukemia and A-549 human adenocarcinoma cells. These semisynthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 through C-19 molecular fragment for potency. Specifically, these analogues suggested the importance of the C-11 and C-17 hydroxyl groups and the C-13 double bond for the potency of discodermolide. The preparation, structure elucidation, and biological activity of these new analogues are described.


Asunto(s)
Alcanos , Antineoplásicos/síntesis química , Carbamatos , Lactonas/síntesis química , Microtúbulos/efectos de los fármacos , Adenocarcinoma , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactonas/química , Lactonas/farmacología , Leucemia P388 , Ratones , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Poríferos/química , Pironas , Relación Estructura-Actividad , Células Tumorales Cultivadas/efectos de los fármacos
17.
J Nat Prod ; 65(11): 1643-8, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12444691

RESUMEN

Discodermolide (1) and five new discodermolide analogues trivially named 2-epi-discodermolide (2), 2-des-methyldiscodermolide (3), 5-hydroxymethyldiscodermolate (4), 19-des-aminocarbonyldiscodermolide (5), and 9(13)-cyclodiscodermolide (6) have been isolated from marine sponges belonging to the genus Discodermia collected from the Caribbean Sea. The isolation, structure elucidation, and biological activities of 2-6 are described. The natural analogues, which were isolated in trace amounts, exhibited significant variation of cytotoxicity against the cultured murine P-388 leukemia and A-549 human adenocarcinoma cells and suggested the importance of the C(7) through C(17) moiety for potency against cultured tumor cell lines.


Asunto(s)
Lactonas/aislamiento & purificación , Poríferos/química , Adenocarcinoma , Animales , Región del Caribe , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactonas/química , Lactonas/farmacología , Leucemia P388 , Ratones , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Relación Estructura-Actividad , Células Tumorales Cultivadas/efectos de los fármacos
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