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1.
Cell ; 184(6): 1589-1603, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33740454

RESUMEN

Vaccines are critical tools for maintaining global health. Traditional vaccine technologies have been used across a wide range of bacterial and viral pathogens, yet there are a number of examples where they have not been successful, such as for persistent infections, rapidly evolving pathogens with high sequence variability, complex viral antigens, and emerging pathogens. Novel technologies such as nucleic acid and viral vector vaccines offer the potential to revolutionize vaccine development as they are well-suited to address existing technology limitations. In this review, we discuss the current state of RNA vaccines, recombinant adenovirus vector-based vaccines, and advances from biomaterials and engineering that address these important public health challenges.


Asunto(s)
Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Adenoviridae/genética , Animales , Antígenos Virales/genética , Materiales Biocompatibles , COVID-19/virología , Sistemas de Liberación de Medicamentos/métodos , Vectores Genéticos/inmunología , Humanos , Inmunogenicidad Vacunal , Liposomas , Nanopartículas , ARN Mensajero/síntesis química , ARN Mensajero/inmunología , Vacunas de ARNm
2.
Mol Ther ; 25(6): 1316-1327, 2017 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-28457665

RESUMEN

Recently, the World Health Organization confirmed 120 new human cases of avian H7N9 influenza in China resulting in 37 deaths, highlighting the concern for a potential pandemic and the need for an effective, safe, and high-speed vaccine production platform. Production speed and scale of mRNA-based vaccines make them ideally suited to impede potential pandemic threats. Here we show that lipid nanoparticle (LNP)-formulated, modified mRNA vaccines, encoding hemagglutinin (HA) proteins of H10N8 (A/Jiangxi-Donghu/346/2013) or H7N9 (A/Anhui/1/2013), generated rapid and robust immune responses in mice, ferrets, and nonhuman primates, as measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays. A single dose of H7N9 mRNA protected mice from a lethal challenge and reduced lung viral titers in ferrets. Interim results from a first-in-human, escalating-dose, phase 1 H10N8 study show very high seroconversion rates, demonstrating robust prophylactic immunity in humans. Adverse events (AEs) were mild or moderate with only a few severe and no serious events. These data show that LNP-formulated, modified mRNA vaccines can induce protective immunogenicity with acceptable tolerability profiles.


Asunto(s)
Subtipo H10N8 del Virus de la Influenza A/genética , Subtipo H10N8 del Virus de la Influenza A/inmunología , Subtipo H7N9 del Virus de la Influenza A/genética , Subtipo H7N9 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae/prevención & control , ARN Mensajero/genética , Animales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Línea Celular , Modelos Animales de Enfermedad , Femenino , Hurones , Expresión Génica , Humanos , Inmunización , Esquemas de Inmunización , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/efectos adversos , Macaca fascicularis , Masculino , Ratones , Protaminas , ARN Mensajero/administración & dosificación , ARN Mensajero/farmacocinética , ARN Viral , Distribución Tisular
3.
Mol Ther ; 25(12): 2635-2647, 2017 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-28958578

RESUMEN

mRNA vaccines are rapidly emerging as a powerful platform for infectious diseases because they are well tolerated, immunogenic, and scalable and are built on precise but adaptable antigen design. We show that two immunizations of modified non-replicating mRNA encoding influenza H10 hemagglutinin (HA) and encapsulated in lipid nanoparticles (LNP) induce protective HA inhibition titers and H10-specific CD4+ T cell responses after intramuscular or intradermal delivery in rhesus macaques. Administration of LNP/mRNA induced rapid and local infiltration of neutrophils, monocytes, and dendritic cells (DCs) to the site of administration and the draining lymph nodes (LNs). While these cells efficiently internalized LNP, mainly monocytes and DCs translated the mRNA and upregulated key co-stimulatory receptors (CD80 and CD86). This coincided with upregulation of type I IFN-inducible genes, including MX1 and CXCL10. The innate immune activation was transient and resulted in priming of H10-specific CD4+ T cells exclusively in the vaccine-draining LNs. Collectively, this demonstrates that mRNA-based vaccines induce type-I IFN-polarized innate immunity and, when combined with antigen production by antigen-presenting cells, lead to generation of potent vaccine-specific responses.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , ARN Mensajero/genética , ARN Mensajero/inmunología , Vacunas/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Citocinas/metabolismo , Expresión Génica , Inmunización , Inmunofenotipificación , Vacunas contra la Influenza/inmunología , Inyecciones Intradérmicas , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Macaca mulatta , Fenotipo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Vacunas/administración & dosificación
5.
Semin Immunol ; 25(2): 130-45, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23850011

RESUMEN

Formulation science is an unappreciated and often overlooked aspect in the field of vaccinology. In this review we highlight key attributes necessary to generate well characterized adjuvant formulations. The relationship between the adjuvant and the antigen impacts the immune responses generated by these complex biopharmaceutical formulations. We will use 5 well established vaccine adjuvant platforms; alum, emulsions, liposomes, PLG, and particulate systems such as ISCOMS in addition to immune stimulatory molecules such as MPL to illustrate that a vaccine formulation is more than a simple mixture of component A and component B. This review identifies the challenges and opportunities of these adjuvant platforms. As antigen and adjuvant formulations increase in complexity having a well characterized robust formulation will be critical to ensuring robust and reproducible results throughout preclinical and clinical studies.


Asunto(s)
Adyuvantes Farmacéuticos/uso terapéutico , Vacunas , Adyuvantes Farmacéuticos/química , Animales , Química Farmacéutica/métodos , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Humanos
6.
J Infect Dis ; 211(6): 947-55, 2015 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-25234719

RESUMEN

Self-amplifying messenger RNA (mRNA) of positive-strand RNA viruses are effective vectors for in situ expression of vaccine antigens and have potential as a new vaccine technology platform well suited for global health applications. The SAM vaccine platform is based on a synthetic, self-amplifying mRNA delivered by a nonviral delivery system. The safety and immunogenicity of an HIV SAM vaccine encoding a clade C envelope glycoprotein formulated with a cationic nanoemulsion (CNE) delivery system was evaluated in rhesus macaques. The HIV SAM vaccine induced potent cellular immune responses that were greater in magnitude than those induced by self-amplifying mRNA packaged in a viral replicon particle (VRP) or by a recombinant HIV envelope protein formulated with MF59 adjuvant, anti-envelope binding (including anti-V1V2), and neutralizing antibody responses that exceeded those induced by the VRP vaccine. These studies provide the first evidence in nonhuman primates that HIV vaccination with a relatively low dose (50 µg) of formulated self-amplifying mRNA is safe and immunogenic.


Asunto(s)
Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , ARN Viral/inmunología , Vacunas contra el SIDA/administración & dosificación , Inmunidad Adaptativa , Animales , Animales no Consanguíneos , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Cationes , Células Cultivadas , Emulsiones , Infecciones por VIH/inmunología , Inmunidad Celular , Macaca mulatta , Masculino , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
7.
Mol Ther ; 22(12): 2118-2129, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25027661

RESUMEN

Nucleic acid-based vaccines such as viral vectors, plasmid DNA, and mRNA are being developed as a means to address a number of unmet medical needs that current vaccine technologies have been unable to address. Here, we describe a cationic nanoemulsion (CNE) delivery system developed to deliver a self-amplifying mRNA vaccine. This nonviral delivery system is based on Novartis's proprietary adjuvant MF59, which has an established clinical safety profile and is well tolerated in children, adults, and the elderly. We show that nonviral delivery of a 9 kb self-amplifying mRNA elicits potent immune responses in mice, rats, rabbits, and nonhuman primates comparable to a viral delivery technology, and demonstrate that, relatively low doses (75 µg) induce antibody and T-cell responses in primates. We also show the CNE-delivered self-amplifying mRNA enhances the local immune environment through recruitment of immune cells similar to an MF59 adjuvanted subunit vaccine. Lastly, we show that the site of protein expression within the muscle and magnitude of protein expression is similar to a viral vector. Given the demonstration that self-amplifying mRNA delivered using a CNE is well tolerated and immunogenic in a variety of animal models, we are optimistic about the prospects for this technology.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Emulsiones/administración & dosificación , Inmunidad Celular , ARN Mensajero/inmunología , ARN Viral/inmunología , Vacunas de ADN/administración & dosificación , Animales , Cationes , Emulsiones/química , Femenino , Macaca mulatta , Ratones , Ratones Endogámicos BALB C , Conejos , Ratas
8.
Proc Natl Acad Sci U S A ; 109(36): 14604-9, 2012 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-22908294

RESUMEN

Despite more than two decades of research and development on nucleic acid vaccines, there is still no commercial product for human use. Taking advantage of the recent innovations in systemic delivery of short interfering RNA (siRNA) using lipid nanoparticles (LNPs), we developed a self-amplifying RNA vaccine. Here we show that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA. This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors. Given the many positive attributes of nucleic acid vaccines, our results suggest that a comprehensive evaluation of nonviral technologies to deliver self-amplifying RNA vaccines is warranted.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/administración & dosificación , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética , Alphavirus/genética , Análisis de Varianza , Animales , Electroforesis en Gel de Agar , Escherichia coli , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Lípidos/química , Nanopartículas/química , ARN Interferente Pequeño/química , Ratas , Estadísticas no Paramétricas
9.
J Control Release ; 335: 237-246, 2021 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-34019945

RESUMEN

Lipid nanoparticles (LNP) are effective delivery vehicles for messenger RNA (mRNA) and have shown promise for vaccine applications. Yet there are no published reports detailing how LNP biophysical properties can impact vaccine performance. In our hands, a retrospective analysis of mRNA LNP vaccine in vivo studies revealed a relationship between LNP particle size and immunogenicity in mice using LNPs of various compositions. To further investigate this, we designed a series of studies to systematically change LNP particle size without altering lipid composition and evaluated biophysical properties and immunogenicity of the resulting LNPs. While small diameter LNPs were substantially less immunogenic in mice, all particle sizes tested yielded a robust immune response in non-human primates (NHP).


Asunto(s)
Inmunogenicidad Vacunal , Nanopartículas , Animales , Humanos , Lípidos , Ratones , ARN Mensajero , Estudios Retrospectivos
10.
Biomed Eng Online ; 9: 56, 2010 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-20875110

RESUMEN

BACKGROUND: In this study, we have examined local non-viral gene delivery, transfection, and therapeutic efficacy of endothelial nitric oxide synthase (eNOS) encoding plasmid DNA administered using coated stents in a rabbit iliac artery restenosis model. METHODS: Lipopolyplexes (LPPs) with eNOS expressing plasmid DNA were immobilized on stainless steel stents using poly(D,L-lactide-co-glycolide) (PLGA) and type B gelatin coatings. The gene-eluting stents were implanted bilaterally in the denuded iliac arteries and eNOS transfection and therapeutic efficacy were examined 14 days after implantation. RESULTS: The results show that non-viral lipopolyplex-coated stents can efficiently tranfect eNOS locally in the arterial lumen assessed by PCR and ELISA. Human eNOS ELISA levels were significantly raised 24 hours after transfection compared to controls (125 pg eNOS compared to <50 pg for all controls including naked DNA). Local eNOS production suppressed smooth muscle cell proliferation and promoted re-endothelialization of the artery showing a significant reduction in restenosis of 1.75 neointima/media ratio for stents with lipoplexes encoding eNOS compared with 2.3 neointima/media ratio for stents with lipoplexes encosing an empty vector. CONCLUSIONS: These results support the hypothesis that a potent non-viral gene vector encoding for eNOS coated onto a stent can inhibit restenosis through inhibition of smooth muscle cell growth and promotion of a healthy endothelium.


Asunto(s)
Reestenosis Coronaria/genética , Reestenosis Coronaria/terapia , Óxido Nítrico Sintasa de Tipo III/genética , Stents , Transfección/métodos , Animales , Reestenosis Coronaria/metabolismo , Reestenosis Coronaria/patología , ADN/química , ADN/genética , ADN/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Gelatina/química , Humanos , Arteria Ilíaca/metabolismo , Arteria Ilíaca/patología , Inmunohistoquímica , Masculino , Polímeros/química , Conejos , Seguridad , Transgenes/genética
12.
Sci Rep ; 9(1): 11520, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31395915

RESUMEN

Self-emulsification is routinely used for oral delivery of lipophilic drugs in vivo, with the emulsion forming in vivo. We modified this technique to prepare novel oil-in-water emulsions of varying droplet size and composition on bench to enable adjuvanted vaccine delivery. We used these formulations to show that smaller droplets (20 nm) were much less effective as adjuvants for an influenza vaccine in mice than the emulsion droplet size of commercial influenza vaccine adjuvants (~160 nm). This was unexpected, given the many claims in the literature of the advantages of smaller particulates. We also undertook cell-recruitment mechanistic studies at site of injection and draining lymph nodes to directly address the question of why the smaller droplets were less effective. We discovered that emulsion droplet size and composition have a considerable impact on the ability to recruit immune cells to the injection site. We believe that further work is warranted to more extensively explore the question of whether, the smaller is not 'better', is a more common observation for particulate adjuvants.


Asunto(s)
Adyuvantes Farmacéuticos/administración & dosificación , Emulsiones/química , Vacunas contra la Influenza/inmunología , Animales , Anticuerpos Antivirales/biosíntesis , Composición de Medicamentos , Femenino , Inmunidad Celular , Vacunas contra la Influenza/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Tamaño de la Partícula
13.
Mol Ther Nucleic Acids ; 15: 1-11, 2019 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-30785039

RESUMEN

mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver. Here, we screened a panel of proprietary biodegradable ionizable lipids for both expression and immunogenicity in a rodent model when administered IM. A subset of compounds was selected and further evaluated for tolerability, immunogenicity, and expression in rodents and non-human primates (NHPs). A lead formulation was identified that yielded a robust immune response with improved tolerability. More importantly for vaccines, increased innate immune stimulation driven by LNPs does not equate to increased immunogenicity, illustrating that mRNA vaccine tolerability can be improved without affecting potency.

14.
J Pharm Sci ; 107(9): 2310-2314, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29883663

RESUMEN

Adjuvants are required to enhance immune responses to typically poorly immunogenic recombinant antigens. Toll-like receptor agonists (TLRa) have been widely evaluated as adjuvants because they activate the innate immune system. Currently, licensed vaccines adjuvanted with TLRa include the TLR4 agonist monophosphoryl lipid, while additional TLRa are in clinical development. Unfortunately, naturally derived TLRa are often complex and heterogeneous entities, which brings formulation challenges. Consequently, the use of synthetic small-molecule TLRa has significant advantages because they are well-defined discrete molecules, which can be chemically modified to modulate their physicochemical properties. We previously described the discovery of a family of TLR7 agonists based on a benzonaphthyridine scaffold. In addition, we described how Alum could be used to deliver these synthetic TLRa. An alternative adjuvant approach with enhanced potency over Alum are squalene containing oil-in-water emulsions, which have been included in licensed influenza vaccines, including Fluad (MF59 adjuvanted) and Pandemrix (AS03 adjuvanted). Here, we describe how to enable the co-delivery of a TLR7 agonist in a squalene-based oil-in-water emulsion, for adjuvant evaluation.


Asunto(s)
Antígenos Bacterianos/administración & dosificación , Antígenos Bacterianos/inmunología , Sistemas de Liberación de Medicamentos/métodos , Emulsiones/administración & dosificación , Inmunidad Celular/inmunología , Nanocápsulas/administración & dosificación , Animales , Estabilidad de Medicamentos , Femenino , Inmunidad Celular/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C
15.
Methods Mol Biol ; 1494: 1-13, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27718182

RESUMEN

Adjuvants are included in sub-unit or recombinant vaccines to enhance the potency of poorly immunogenic antigens. Adjuvant discovery is as complex as it is a multidiscplinary intersection of formulation science, immunology, toxicology, and biology. Adjuvants such as alum, which have been in use for the past 90 years, have illustrated that adjuvant research is a methodical process. As science advances, new analytical tools are developed which allows us to delve deeper into the various mechanisms that generates a potent immune response. Additionally, these new techniques help the field learn about our existing vaccines and what makes them safe, and effective, allowing us to leverage that in the next generation of vaccines. Our goal in this chapter is to define the concept, need, and mechanism of adjuvants in the vaccine field while describing its history, present use, and future prospects. More details on individual adjuvants and their formulation, development, mechanism, and use will be covered in depth in the next chapters.


Asunto(s)
Adyuvantes Inmunológicos , Compuestos de Alumbre , Vacunas , Adyuvantes Inmunológicos/historia , Adyuvantes Inmunológicos/uso terapéutico , Compuestos de Alumbre/historia , Compuestos de Alumbre/uso terapéutico , Animales , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Vacunas/historia , Vacunas/uso terapéutico
16.
Front Immunol ; 8: 1539, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29181005

RESUMEN

Modified mRNA vaccines have developed into an effective and well-tolerated vaccine platform that offers scalable and precise antigen production. Nevertheless, the immunological events leading to strong antibody responses elicited by mRNA vaccines are largely unknown. In this study, we demonstrate that protective levels of antibodies to hemagglutinin were induced after two immunizations of modified non-replicating mRNA encoding influenza H10 encapsulated in lipid nanoparticles (LNP) in non-human primates. While both intradermal (ID) and intramuscular (IM) administration induced protective titers, ID delivery generated this response more rapidly. Circulating H10-specific memory B cells expanded after each immunization, along with a transient appearance of plasmablasts. The memory B cell pool waned over time but remained detectable throughout the 25-week study. Following prime immunization, H10-specific plasma cells were found in the bone marrow and persisted over time. Germinal centers were formed in vaccine-draining lymph nodes along with an increase in circulating H10-specific ICOS+ PD-1+ CXCR3+ T follicular helper cells, a population shown to correlate with high avidity antibody responses after seasonal influenza vaccination in humans. Collectively, this study demonstrates that mRNA/LNP vaccines potently induce an immunological repertoire associated with the generation of high magnitude and quality antibodies.

17.
J Pharm Sci ; 104(4): 1352-61, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25600347

RESUMEN

Microfluidization is an established technique for preparing emulsion adjuvant formulations for use in vaccines. Although this technique reproducibly yields high-quality stable emulsions, it is complex, expensive, and requires proprietary equipment. For this study, we developed a novel and simple low shear process to prepare stable reproducible emulsions without the use of any proprietary equipment. We found this process can produce a wide range of differently sized emulsions based on the modification of ratios of oil and surfactants. Using this process, we prepared a novel 20-nm-sized emulsion that was stable, reproducible, and showed adjuvant effects. During evaluation of this emulsion, we studied a range of emulsions with the same composition all sized below 200; 20, 90, and 160 nm in vivo and established a correlation between adjuvant size and immune responses. Our studies indicate that 160-nm-sized emulsions generate the strongest immune responses.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Vacunas contra la Influenza/inmunología , Aceites/farmacología , Ovalbúmina/inmunología , Agua/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/química , Animales , Anticuerpos/sangre , Biomarcadores/sangre , Células Cultivadas , Química Farmacéutica , Emulsiones , Femenino , Inmunidad Humoral/efectos de los fármacos , Inmunización , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/química , Inyecciones Intramusculares , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microfluídica , Nanopartículas , Aceites/administración & dosificación , Aceites/química , Ovalbúmina/administración & dosificación , Ovalbúmina/química , Tamaño de la Partícula , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Tecnología Farmacéutica/métodos , Factores de Tiempo , Agua/administración & dosificación , Agua/química
18.
Adv Genet ; 89: 179-233, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25620012

RESUMEN

This chapter provides a brief introduction to nucleic acid-based vaccines and recent research in developing self-amplifying mRNA vaccines. These vaccines promise the flexibility of plasmid DNA vaccines with enhanced immunogenicity and safety. The key to realizing the full potential of these vaccines is efficient delivery of nucleic acid to the cytoplasm of a cell, where it can amplify and express the encoded antigenic protein. The hydrophilicity and strong net negative charge of RNA impedes cellular uptake. To overcome this limitation, electrostatic complexation with cationic lipids or polymers and physical delivery using electroporation or ballistic particles to improve cellular uptake has been evaluated. This chapter highlights the rapid progress made in using nonviral delivery systems for RNA-based vaccines. Initial preclinical testing of self-amplifying mRNA vaccines has shown nonviral delivery to be capable of producing potent and robust innate and adaptive immune responses in small animals and nonhuman primates. Historically, the prospect of developing mRNA vaccines was uncertain due to concerns of mRNA instability and the feasibility of large-scale manufacturing. Today, these issues are no longer perceived as barriers in the widespread implementation of the technology. Currently, nonamplifying mRNA vaccines are under investigation in human clinical trials and can be produced at a sufficient quantity and quality to meet regulatory requirements. If the encouraging preclinical data with self-amplifying mRNA vaccines are matched by equivalently positive immunogenicity, potency, and tolerability in human trials, this platform could establish nucleic acid vaccines as a versatile new tool for human immunization.


Asunto(s)
ARN Mensajero/administración & dosificación , Vacunas/administración & dosificación , Animales , Antígenos/genética , Electroporación , Humanos , Nanopartículas/administración & dosificación , Nanopartículas/química , ARN Mensajero/efectos adversos , ARN Mensajero/genética , Vacunas/efectos adversos , Vacunas Virales
19.
J Control Release ; 190: 563-79, 2014 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-24998942

RESUMEN

Vaccine adjuvants interact with the immune system, to increase the potency of vaccine antigens. Many of the adjuvants currently available were developed with little understanding of how they worked. Highly pure recombinant antigens are typically very poorly immunogenic due to a lack of exogenous immune activating components such as nucleic acids, lipids, and cell membrane components. In this review we discuss the role of adjuvants and their role as 'delivery systems' or 'immune potentiators'. We also highlight the need for appropriate delivery of immune potentiators with several 'delivery system' adjuvants such as alum, emulsions, liposomes, and polymeric particles. The challenges faced by vaccinologists to create the next generation of vaccines can be solved in-part by developing a greater understanding of the impact of delivery, and an appreciation of the key role of pharmaceutical sciences.


Asunto(s)
Adyuvantes Inmunológicos , Compuestos de Alumbre , Liposomas , Vacunas/inmunología , Adyuvantes Inmunológicos/historia , Compuestos de Alumbre/historia , Compuestos de Alumbre/farmacología , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos , Emulsiones/historia , Historia del Siglo XX , Humanos , Liposomas/historia , Nanopartículas
20.
Expert Opin Drug Deliv ; 11(6): 885-99, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24665982

RESUMEN

INTRODUCTION: Nucleic acid-based vaccines are being developed as a means to combine the positive attributes of both live-attenuated and subunit vaccines. Viral vectors and plasmid DNA vaccines have been extensively evaluated in human clinical trials and have been shown to be safe and immunogenic, although none have been licensed for human use. More recently, mRNA-based vaccine alternatives have emerged and might offer certain advantages over their DNA-based counterparts. AREAS COVERED: This review describes the two main categories of mRNA vaccines: conventional non-amplifying and self-amplifying mRNA. It summarizes the initial clinical proof-of-concept studies and outlines the preclinical testing of the next wave of innovations for the technology. Finally, this review highlights the versatile functionality of the mRNA molecule and introduces opportunities for future improvements in vaccine design. EXPERT OPINION: The prospects for mRNA vaccines are very promising. Like other types of nucleic acid vaccines, mRNA vaccines have the potential to combine the positive attributes of live attenuated vaccines while obviating many potential safety limitations. Although data from initial clinical trials appear encouraging, mRNA vaccines are far from a commercial product. These initial approaches have spurred innovations in vector design, non-viral delivery, large-scale production and purification of mRNA to quickly move the technology forward. Some improvements have already been tested in preclinical models for both prophylactic and therapeutic vaccine targets and have demonstrated their ability to elicit potent and broad immune responses, including functional antibodies, type 1 T helper cells-type T cell responses and cytotoxic T cells. Though the initial barriers for this nucleic acid vaccine approach seem to be overcome, in our opinion, the future and continued success of this approach lies in a more extensive evaluation of the many non-viral delivery systems described in the literature and gaining a better understanding of the mechanism of action to allow rational design of next generation technologies.


Asunto(s)
Sistemas de Liberación de Medicamentos , ARN Mensajero/inmunología , Vacunas de ADN/administración & dosificación , Animales , Vectores Genéticos , Humanos , Plásmidos
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