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BACKGROUND: Modified balloon (MB) treatment in severely calcified coronary artery lesions is an established technique. However, some lesions require Rotablation (RA) as bailout strategy. AIMS: This study aimed to assess predictors of switch from MB to RA and its impact on procedural and midterm outcomes. METHODS: Four hundred and eighty-three consecutive patients were included undergoing MB treatment (n = 204) with a scoring or cutting balloon, or upfront RA treatment (n = 279) serving as control cohort. Strategy switch from MB to RA was performed in 19 of 204 patients. Procedural success was defined as successful stent implantation and TIMI III flow. RESULTS: In the MB cohort, median age was 72 [63-78] years, 75.5% were male and 42.1% had acute coronary syndrome. Procedure success was achieved in 89.4% of the switch group versus 98.4% of the MB only group (p < 0.001) and in 96.4% of the RA cohort. In the switch group, periprocedural complications (31.6% vs. 8.1% vs. 11.8%, p = 0.007), radiation dose (149 [126-252] vs. 59 [30-97] vs. 102 [59-156] Gcm2; p < 0.001) and contrast volume (250 [190-250] vs. 190 [150-250] vs. 195 [190--250] mL; p < 0.001) were significantly higher. Diabetes (OR 3.8, 95% CI 1.1-13.9, p = 0.042), chronic kidney disease stage 4 or 5 (OR 19.0, 95% CI 3.3-108.6, p < 0.001) and pronounced calcification resulting in higher angiographic diameter stenosis (OR 1.13, 95% CI 1.1-1.2, p = 0.001) independently predicted strategy switch. Midterm results were not affected by strategy switch regarding 1-year target lesion revascularization rates (86% vs. 89% vs. 89%; log-rank p = 0.95). CONCLUSION: Primary RA strategy might be considered in patients with severely calcified coronary artery lesions with high angiographic diameter stenosis, diabetes or impaired renal function due to increased periprocedural complication rates, radiation dose, and contrast volume following strategy switch.
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With the rapid progress made in the development of vaccines to fight the SARS-CoV-2 pandemic, almost >90% of vaccine candidates under development and a 100% of the licensed vaccines are delivered intramuscularly (IM). While these vaccines are highly efficacious against COVID-19 disease, their efficacy against SARS-CoV-2 infection of upper respiratory tract and transmission is at best temporary. Development of safe and efficacious vaccines that are able to induce robust mucosal and systemic immune responses are needed to control new variants. In this study, we have used our nanoemulsion adjuvant (NE01) to intranasally (IN) deliver stabilized spike protein (S-2P) to induce immunogenicity in mouse and hamster models. Data presented demonstrate the induction of robust immunity in mice resulting in 100% seroconversion and protection against SARS-CoV-2 in a hamster challenge model. There was a significant induction of mucosal immune responses as demonstrated by IgA- and IgG-producing memory B cells in the lungs of animals that received intranasal immunizations compared to an alum adjuvanted intramuscular vaccine. The efficacy of the S-2P/NE01 vaccine was also demonstrated in an intranasal hamster challenge model with SARS-CoV-2 and conferred significant protection against weight loss, lung pathology, and viral clearance from both upper and lower respiratory tract. Our findings demonstrate that intranasal NE01-adjuvanted vaccine promotes protective immunity against SARS-CoV-2 infection and disease through activation of three arms of immune system: humoral, cellular, and mucosal, suggesting that an intranasal SARS-CoV-2 vaccine may play a role in addressing a unique public health problem and unmet medical need.
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COVID-19 , Inmunidad Mucosa , Ratones , Humanos , Animales , Cricetinae , Vacunas contra la COVID-19 , Anticuerpos Antivirales , COVID-19/prevención & control , SARS-CoV-2 , Adyuvantes Inmunológicos , Administración Intranasal , Anticuerpos Neutralizantes , Glicoproteína de la Espiga del CoronavirusRESUMEN
Intramuscular vaccines have greatly reduced hospitalization and death due to severe COVID-19. However, most countries are experiencing a resurgence of infection driven predominantly by the Delta and Omicron variants of SARS-CoV-2. In response, booster dosing of COVID-19 vaccines has been implemented in many countries to address waning immunity and reduced protection against the variants. However, intramuscular boosting fails to elicit mucosal immunity and therefore does not solve the problem of persistent viral carriage and transmission, even in patients protected from severe disease. In this study, two doses of stabilized prefusion SARS-CoV-2 spike (S-2P)-based intramuscular vaccine adjuvanted with Alum/CpG1018, MVC-COV1901, were used as a primary vaccination series, followed by an intranasal booster vaccination with nanoemulsion (NE01)-adjuvanted S-2P vaccine in a hamster model to demonstrate immunogenicity and protection from viral challenge. Here we report that this vaccination regimen resulted not only in the induction of robust immunity and protection against weight loss and lung pathology following challenge with SARS-CoV-2, but also led to increased viral clearance from both upper and lower respiratory tracts. Our findings showed that intramuscular MVC-COV1901 vaccine followed by a booster with intranasal NE01-adjuvanted vaccine promotes protective immunity against both viral infection and disease, suggesting that this immunization protocol may offer a solution in addressing a significant, unmet medical need for both the COVID-19 and future pandemics.
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COVID-19 , Vacunas Virales , Adyuvantes Inmunológicos , Animales , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Cricetinae , Humanos , SARS-CoV-2RESUMEN
BACKGROUND: Staphylococcus aureus is a commensal of human skin and nares. It is also one of the leading nosocomial pathogens in both developed and developing countries and is responsible for a wide range of life threatening infections, especially in patients who are immunocompromised, post-surgery, undergoing haemodialysis and those who are treated with catheters and ventilators. Over the past two decades, the incidence of nosocomial staphylococcal infections has increased dramatically. Currently there are at least seven vaccine and immunotherapy candidates against S. aureus in the developmental phase targeting both active and passive immunization. METHODS: We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging vaccines against Staphylococcus aureus relevant to several criteria of interest: answerability; cost of development, production and implementation; efficacy and effectiveness; deliverability, affordability and sustainability; maximum potential impact on disease burden reduction; acceptability to the end users and health workers; and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies) to participate. The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to sensitive nature of their involvement in such exercises. They answered questions from CHNRI framework and their "collective optimism" towards each criterion was documented on a scale from 0 to 100%. RESULTS: The panel of experts expressed low levels of optimism (score around or below 50%) on the criteria of answerability, efficacy, maximum disease burden reduction potential, low cost of production, low cost of implementation and affordability; moderate levels of optimism (scores around 60 to 80%) that these vaccines could be developed at a low cost, and thus on the deliverability, sustainability and impact on equity; and high levels of optimism (scores above 80%) regarding acceptable of such a product to both the end-users and health workers. While assessing the candidates for passive immunization against S.aureus, the experts were poorly optimistic regarding low production cost, low implementation cost, efficacy, deliverability, sustainability, affordability and equity; moderately optimistic regarding answerability and acceptability to health workers and end-users. They were of the opinion that these interventions would have only a modest impact (3 to 5%) on the burden of childhood pneumonia. . CONCLUSION: In order to provide an effective vaccine against S. aureus, a number of unresolved issues in vaccine development relating to optimal antigenic target identification, criteria for acceptable efficacy, identification of target population, commercial development limitations, optimal timing of immunization strategy, storage, cold chain requirements and cost need to be addressed properly. There is still a great deal unknown about the complex interaction between S. aureus and the human host. However, given the nature of S. aureus and the lessons learned from the recent failure of two emerging vaccines, it is clear that a multi-component vaccine is essential. Combating only one virulence factor is not sufficient in the human host but finding the right combination of factors will be very challenging.
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Inmunoterapia , Neumonía Estafilocócica/terapia , Vacunas Estafilocócicas , Staphylococcus aureus/inmunología , Niño , Humanos , Neumonía Estafilocócica/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Vacunas Estafilocócicas/provisión & distribución , Resultado del TratamientoRESUMEN
INTRODUCTION: Nicotine immunization is under consideration as an intervention for smoking cessation. Therefore, it was of interest to evaluate the effects of nicotine antibodies on the withdrawal syndrome following termination of chronic nicotine administration. METHODS: Experiment 1 determined whether passive immunization following continuous nicotine infusion would alter the intensity of nicotine withdrawal syndrome in the rat. Fourteen rats were rendered nicotine dependent by 7 days of subcutaneous nicotine bitartrate infusion. On the final day, seven rats received 150 mg intraperitoneal (i.p.) of immune gamma globulin (IgG) raised against 3'-aminomethylnicotine-recombinant Pseudomonas aeruginosa exoprotein A (NicVAX, Nabi Biopharmaceuticals, Rockville, MD) and seven rats received normal IgG. Rats were observed under blind conditions for somatically expressed nicotine abstinence signs immediately prior to drug termination and at 12, 24, and 36 hr afterward. In Experiment 2, similarly treated rats were observed at 6- and 72-hr postwithdrawal, to test the possibility that immunization altered the time course rather than the intensity of withdrawal syndrome. Experiment 3 tested whether immunized rats were still nicotine dependent. Without pump removal, each rat was challenged by 1/mg/kg mecamylamine HCl and observed for precipitated withdrawal syndrome. RESULTS: In Experiment 1, there was no premature withdrawal syndrome during nicotine infusion. After termination, the immunized group had significantly fewer withdrawal signs than controls. Experiment 2 showed that immunization did not simply alter the timing of the nicotine abstinence syndrome since immunization did not increase signs before or after the usual withdrawal timeframe. In Experiment 3, rats immunized on the final day of infusion were still nicotine dependent since they exhibited a vigorous mecamylamine-precipitated withdrawal syndrome. DISCUSSION: Nicotine antibodies did not precipitate a withdrawal syndrome, and they markedly reduced the severity of spontaneous nicotine withdrawal. The present data suggests that this may be most readily explained by their reported delay of nicotine clearance.
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Inmunización Pasiva/métodos , Nicotina/inmunología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Tabaquismo/inmunología , Tabaquismo/prevención & control , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/inmunologíaRESUMEN
BACKGROUND: Vaccination is the most effective approach to prevent infection with highly pathogenic avian influenza (HPAI). Adjuvants are often used to induce effective immune responses and overcome the immunological weakness of recombinant HPAI antigens. Given the logistical challenges of immunization to HPAI during pandemic situations, vaccines administered via the intramuscular (I.M.) route would be of value. METHODS: A new formulation of nanoemulsion adjuvant (NE02) suitable for I.M. vaccination was developed. This NE02 was evaluated alone and in combination with CpG to develop H5 immune responses in mouse and ferret models. Measures of recombinant H5 (rH5) specific immunity evaluated included serum IgG and IgG subclasses, bronchoalveolar lavage fluid IgA, and cytokines. The activation of NF-kB was also analyzed. The efficacy of the vaccine was assessed by performing hemagglutination inhibition (HAI), virus neutralization (VN) assays, and viral challenges in ferrets. RESULTS: I.M. vaccination with rH5-NE02 significantly increased rH5-specific IgG and protected ferrets in the viral challenge model providing complete protection and sterile immunity in all animals tested. Combining NE02 and CpG produced accelerated antibody responses and this was accompanied by an elevation of IFN-γ and IL-17 responses and the downregulation of IL-5. The combination also caused a synergistic effect on NF-kB activation. In immunized ferrets after viral challenge, the rH5-NE02â¯+â¯CpG vaccine via I.M. achieved at least 75% and 88% seroconversion of HAI and VN antibody responses, respectively, and improved body temperature stabilization and weight loss over NE02 alone. CONCLUSIONS: The I.M. injection of NE02 adjuvanted rH5 elicits strong and broad immune responses against H5 antigens and effectively protects animals from lethal H5 challenge. Combining this adjuvant with CpG enhanced immune responses and provided improvements in outcomes to viral challenge in ferrets. The results suggest that combinations of adjuvants may be useful to enhance H5 immune responses and improve protection against influenza infection.
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Subtipo H5N1 del Virus de la Influenza A , Virus de la Influenza A , Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Adyuvantes Inmunológicos , Animales , Anticuerpos Antivirales , Hurones , Ratones , Infecciones por Orthomyxoviridae/prevención & controlRESUMEN
BACKGROUND: Flu vaccines administered intramuscularly (IM) have shown seasonally fluctuating efficacy, 20-60%, throughout the last 15â¯years. We formulated a recombinant H5 (rH5) in our Nanovax® (NE01) (rH5/NE01) adjuvant for intranasal vaccination in ferrets. We evaluated the regimen, one vs two immunization, and cross clade protection a ferret challenge model. METHODS: Plant derived recombinant H5 (rH5) antigen was formulated with NE01 and administered intranasally to ferrets. Immunogenicity (IgG), hemagglutination inhibition (HI), and protection against lethal challenge, were measured following one or two immunizations. Protection against homologous (strain A/Indo) and heterologous (strain A/Vn) was evaluated in ferrets following two immunizations. RESULTS: IN immunization with rH5/NE01 induced significant IgG levels after one and two immunizations. One vaccination did not induce any HI while low HI was measured after two immunizations. Homologous challenge with H5N1 A/ Indonesia showed 100% survival, with minimal weight loss in animals vaccinated twice compared to the unvaccinated controls. Analysis of nasal wash from these challenged ferrets vaccinated twice showed decreased viral shedding compared to unvaccinated controls. Interestingly, animals that received one vaccination showed 88% survival with moderate weight loss. Cross clade protection was evaluated using an increased antigen dose (45⯵g rH5). Vaccinated animals demonstrated increased IgG and HAI antibody responses. Both homologous (A/Indo) and heterologous challenge (A/Vietnam) following two immunizations showed 100% survival with no loss of body weight. However viral clearance was more rapid against the homologous (day 3) compared to the heterologous (day 5) post challenge. CONCLUSION: Intranasal administration of NE01 adjuvant-formulated rH5 vaccine elicited systemic and probably mucosal immunity that conferred protection against lethal challenge with homologous or heterologous viral strains. It also enhanced viral clearance with decreased shedding. These outcomes strongly suggest that intranasal immunization using NE01 against flu infections warrants clinical testing.
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Anticuerpos Antivirales/sangre , Hurones/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Subtipo H5N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae/veterinaria , Adyuvantes Inmunológicos , Administración Intranasal , Animales , Anticuerpos Neutralizantes/sangre , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Inmunidad Mucosa/inmunología , Inmunización Secundaria , Inmunoglobulina G/sangre , Infecciones por Orthomyxoviridae/prevención & control , Proteínas Recombinantes/inmunología , Vacunación , Vacunas Sintéticas/inmunologíaRESUMEN
Genital herpes is a sexually transmitted disease representing a major global health concern. Currently, there is no approved vaccine and existing antiviral therapies exhibit limited efficacy. Herein, we describe an intranasal (IN) vaccine comprised of HSV-2 surface glycoproteins gD2 and gB2 formulated in a nanoemulsion adjuvant (NE01-gD2/gB2). Using the HSV-2 genital herpes guinea pig model, we demonstrate that IN NE01-gD2/gB2 induces higher levels of neutralizing antibody compared to a monovalent IN NE01-gD2 vaccine, but less than an intramuscular (IM) Alum/MPL-gD2 vaccine. Following intravaginal (IVag) challenge with HSV-2, the group immunized with IN NE01-gD2/gB2 exhibited significantly reduced acute and recurrent disease scores compared to placebo recipients. Significantly, latent virus was only detected in the dorsal root ganglia of 1 of 12 IN NE01-gD2/gB2-vaccinated animals compared to 11 of 12 placebo recipient. In the therapeutic model, IN NE01-gD2/gB2 immunized guinea pigs exhibited a significant reduction in the recurrent lesions scores (64%, pâ¯<â¯0.01), number of animal days with disease (64%, pâ¯<â¯0.01), number of animals with viral shedding (50%, pâ¯<â¯0.04) and reduction in virus positive vaginal swabs (56%, pâ¯<â¯0.04), These data suggests that the treatment may be effective in treating chronic disease and minimizing virus transmission. These results warrant advancing the development of IN NE01-gD2/gB2 as both a prophylactic and therapeutic vaccine against HSV-2.
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Anticuerpos Antivirales/sangre , Herpes Genital/prevención & control , Herpes Genital/terapia , Vacunas contra el Virus del Herpes Simple/administración & dosificación , Vacunas contra el Virus del Herpes Simple/uso terapéutico , Adyuvantes Inmunológicos/administración & dosificación , Administración Intranasal , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Modelos Animales de Enfermedad , Emulsiones/administración & dosificación , Emulsiones/química , Femenino , Cobayas , Herpes Genital/inmunología , Herpesvirus Humano 2 , Nanopartículas/administración & dosificación , Nanopartículas/química , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/uso terapéutico , Esparcimiento de VirusRESUMEN
BACKGROUND: Highly pathogenic H5N1 influenza viruses remain a pandemic risk to the world population. Although vaccines are the best solution to prevent this threat, a more effective vaccine for H5 strains of influenza has yet to be developed. All existing vaccines target only serum antibody against influenza as the primary outcome, while mucosal immunity has not been addressed. To address these shortcomings we have used an effective mucosal adjuvant system to produce a prototype vaccine that provides antibody, cellular and mucosal immunity to multiple serotypes of H5. METHODS: Plant-derived recombinant H5 (rH5) antigen was mixed with a novel nanoemulsion NE01 adjuvant. The rH5-NE01 vaccine was administered intranasally to CD-1 mice and ferrets. Immunogenicity of this immunization was evaluated through rH5-specific antibody and cellular immune responses. Hemagglutination inhibition (HI) and virus neutralization (VN) assays were performed. Protection against H5N1 virus challenge was evaluated in ferrets. RESULTS: Intranasal immunization with rH5-NE01vaccine induced high titers (>106) of rH5-specific IgG in mice. In mice and ferrets this vaccine also achieved titers of ≥40 for both HI and VN. Additionally, the levels of rH5-specific IgA were significantly increased in bronchial secretions in these animals. The rH5-NE01 vaccine enhanced rH5-specific cellular immune responses including IFN-γ and IL-17. Ten-day survival post challenge was 100% in ferrets that received rH5-NE01compared to 12.5% in the PBS group. Furthermore, this vaccine prevented weight loss and increases in body temperature after H5N1 challenge as compared to the controls. Moreover, H5N1 virus in nasal wash of rH5-NE01-vaccinated ferrets was significantly decreased compared to controls. CONCLUSION: Intranasal immunization with rH5 antigen formulated with NE01 adjuvant elicited strong, broad and balanced immune responses that effectively protect against H5N1 influenza virus infection in the ferret model. The ease of formulation of rH5-NE01 makes this novel combination a promising mucosal vaccine candidate for pandemic influenza.
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Adyuvantes Inmunológicos , Emulsiones , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae/inmunología , Animales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Citocinas/metabolismo , Femenino , Hurones , Glicoproteínas Hemaglutininas del Virus de la Influenza/administración & dosificación , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Inmunización , Inmunogenicidad Vacunal , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Subtipo H5N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/química , Masculino , Ratones , Infecciones por Orthomyxoviridae/prevención & control , Proteínas RecombinantesRESUMEN
International epidemiological studies have shown that clinical isolates of Staphylococcus aureus are usually capsulated with either type 5 or 8 capsular polysaccharides (CPs). Because all noncapsulated strains were found to be cross-reactive with polysaccharide 336 (336PS) antibodies, the noncapsulated strains were denoted as type 336PS. The capsular types of 162 Dutch methicillin-susceptible S. aureus strains derived from individuals living in the Rotterdam area were determined. The serotype distribution was 28.4% serotype 5, 53.7% type 8, and 17.9% type 336PS. Serotyping was in agreement with genotyping by amplified fragment length polymorphism (AFLP) and multi locus sequence typing (MLST). Among 49 nasal carriage isolates from healthy children 24.5% belonged to serotype 5, 67.3% were type 8 and 8.2% were type 336PS. For 28 adult patients on chronic ambulatory peritoneal dialysis (CAPD) the serotype incidences among carriage isolates obtained from the nose, catheter exit-site, and abdominal skin were 45.1%, 41.2% and 13.7%, respectively. Among S. aureus strains deriving from blood cultures, the serotype incidences were 17.7% serotype 5, 53.2% type 8, and 29.0% type 336PS. Apparently, type 336PS strains are more prevalent (P=0.017) among bacteraemia isolates as compared with the nasal carriage isolates obtained from healthy children and CAPD patients. In conclusion, all Dutch S. aureus isolates belonged to types 5, 8, or 336PS, which is in agreement with data from other countries. Thus, addition of the 336PS conjugate to a type 5- and type 8-CP protein conjugate vaccine would significantly extend the vaccine coverage.
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Portador Sano/microbiología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/clasificación , Análisis del Polimorfismo de Longitud de Fragmentos Amplificados , Cápsulas Bacterianas/inmunología , Portador Sano/epidemiología , Análisis por Conglomerados , ADN Bacteriano/química , ADN Bacteriano/genética , Genotipo , Humanos , Incidencia , Países Bajos/epidemiología , Nariz/microbiología , Análisis de Secuencia de ADN , Serotipificación , Infecciones Estafilocócicas/epidemiología , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
BACKGROUND: In patients with decreased resistance to infection, Staphylococcus aureus is a major cause of bacteremia and its complications. The capsular polysaccharides are essential for the pathogenesis of and immunity to S. aureus infection and are targets for vaccines. METHODS: In a double-blind trial involving patients with end-stage renal disease who were receiving hemodialysis, we evaluated the safety, immunogenicity, and efficacy of a vaccine with S. aureus type 5 and 8 capsular polysaccharides conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A. Between April 1998 and August 1999, 1804 adult patients at 73 hemodialysis centers were randomly assigned to receive a single intramuscular injection of either vaccine or saline. IgG antibodies to S. aureus type 5 and 8 capsular polysaccharides were measured for up to two years, and episodes of S. aureus bacteremia were recorded. Efficacy was estimated by comparing the incidence of S. aureus bacteremia in the patients who received the vaccine with the incidence in the control patients. RESULTS: Reactions to the vaccine were generally mild to moderate, and most resolved within two days. The capsular polysaccharides elicited an antibody response of at least 80 microg per milliliter (the estimated minimal level conferring protection) in 80 percent of patients for type 5 and in 75 percent of patients for type 8. The efficacy during weeks 3 to 54 was only 26 percent (P=0.23). However, between weeks 3 and 40 after vaccination, S. aureus bacteremia developed in 11 of 892 patients in the vaccine group who could be evaluated for bacteremia, as compared with 26 of 906 patients in the control group (estimate of efficacy, 57 percent; 95 percent confidence interval, 10 to 81 percent; nominal P=0.02). CONCLUSIONS: In patients receiving hemodialysis, a conjugate vaccine can confer partial immunity against S. aureus bacteremia for approximately 40 weeks, after which protection wanes as antibody levels decrease.
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Bacteriemia/prevención & control , Vacunas Bacterianas , Fallo Renal Crónico/complicaciones , Diálisis Renal , Infecciones Estafilocócicas/prevención & control , Vacunas Estafilocócicas , Adulto , Anticuerpos Antibacterianos/sangre , Bacteriemia/etiología , Vacunas Bacterianas/efectos adversos , Vacunas Bacterianas/inmunología , Método Doble Ciego , Humanos , Fallo Renal Crónico/terapia , Infecciones Estafilocócicas/etiología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/clasificación , Staphylococcus aureus/inmunología , Staphylococcus aureus/aislamiento & purificación , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/inmunologíaRESUMEN
Because of its ability to cause serious and fatal infections, Staphylococcus aureus remains one of the most feared microorganisms. Methicillin-resistant S. aureus (MRSA) has long been a common pathogen in healthcare facilities, but within the past decade, it has emerged as a problematic pathogen in the community setting as well. The severe consequences of infection heighten the importance of prevention. To analyze the potential applicability of a putative S. aureus polysaccharide conjugate vaccine, we tested 714 German methicillin-susceptible S. aureus (MSSA) and MRSA strains for their capsular and surface polysaccharide serotype by slide agglutination with specific antibodies (anti-T5-DT, anti-T8-DT, anti-336-rEPA). The strain serotypes were confirmed by immunodiffusion using lysostaphin-digested cell lysates. Regarding MRSA strains representing 86 unique spa types and thus covering >90% of MRSA spa types registered, 39 (45.3%) were type 5, 36 (41.9%) were type 8, and 11 (12.8%) were type 336. Of particular interest, type 336 was the second most common serotype among MRSA isolates collected from 10 different laboratories (40 isolates per site) covering university hospitals, general hospitals, and clinics throughout Germany. Type 8-positive strains were more prevalent among isolates recovered from anterior nares of patients who did not subsequently develop S. aureus bacteremia compared with those who became bacteremic with this pathogen. In conclusion, the addition of the newly described type 336 to a capsular polysaccharide-protein conjugate vaccine could extend the coverage substantially and would include virtually all MSSA and MRSA strains currently circulating in Germany.
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Polisacáridos Bacterianos/inmunología , Serotipificación , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/clasificación , Staphylococcus aureus/inmunología , Pruebas de Aglutinación , Alemania , Hospitales , Humanos , Inmunodifusión , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is contracted via aerosol infection, typically affecting the lungs. Mycobacterium bovis bacillus Calmette-Guerin (BCG) is the only licensed vaccine and has variable efficacy in protecting against pulmonary TB. Additionally, chemotherapy is associated with low compliance contributing to development of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb. Thus, there is an urgent need for the design of more effective vaccines against TB. Experimental vaccines delivered through the mucosal route induce robust T helper type 17 (Th17)/ Interleukin (IL) -17 responses and provide superior protection against Mtb infection. Thus, the development of safe mucosal adjuvants for human use is critical. In this study, we demonstrate that nanoemulsion (NE)-based adjuvants when delivered intranasally along with Mtb specific immunodominant antigens (NE-TB vaccine) induce potent mucosal IL-17T-cell responses. Additionally, the NE-TB vaccine confers significant protection against Mtb infection, and when delivered along with BCG, is associated with decreased disease severity. These findings strongly support the development of a NE-TB vaccine as a novel, safe and effective, first-of-kind IL-17 inducing mucosal vaccine for potential use in humans.
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Interleucina-17/metabolismo , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Vacunas contra la Tuberculosis/inmunología , Vacunas contra la Tuberculosis/uso terapéutico , Adyuvantes Inmunológicos , Animales , Antígenos Bacterianos/inmunología , Ratones , Ratones Endogámicos C57BL , Tuberculosis/inmunología , Tuberculosis/prevención & controlRESUMEN
We conducted a randomized, double-blind, placebo-controlled dose-escalation study in healthy adults to evaluate the safety and immunogenicity of recombinant Staphylococcus aureus candidate vaccine antigens, recombinant α-toxoid (rAT) and a sub-unit of Panton-Valentine leukocidin (rLukS-PV). 176 subjects were enrolled and randomized within 1 of 11 treatment cohorts: monovalent rAT or rLukS-PV dosages of 10, 25, 50, and 100 µg; bivalent rAT:rLukS dosages of 10:10, 25:25, and 50:50 µg; and alum or saline placebo. All subjects were assessed at Days 0, 7, 14, 28, and 84. Subjects in the 50:50 µg bivalent cohort received a second injection on Day 84 and were assessed on Days 98 and 112. Incidence and severity of reactogenicity and adverse events (AEs) were compared. Geometric mean serum concentrations (GMC) and neutralizing activity of anti-rAT and anti-rLukS-PV IgG were assessed. Reactogenicity incidence was significantly higher in vaccine than placebo recipients (77% versus 55%, respectively; p = 0.006). However, 77% of reactogenicity events were mild and 19% were moderate in severity. The AE incidence and severity were similar between the cohorts. All monovalent and bivalent rAT dosages resulted in a significant increase in the anti-rAT IgG and anti- rLukS-PV GMCs between day 0 and 28 compared with placebo, and persisted through Day 84. Exploratory subgroup analyses suggested a higher GMC and neutralizing antibody titers for the 50 µg monovalent or bivalent rAT and rLukS-PV dose as compared to the other doses. No booster effect was observed after administration of the second dose. We conclude that the rAT and rLukS-PV vaccine formulations were well-tolerated and had a favorable immunogenicity profile, producing antibody with neutralizing activity through day 84. There was no benefit observed with a booster dose of the vaccine.
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Toxinas Bacterianas/inmunología , Exotoxinas/inmunología , Proteínas Hemolisinas/inmunología , Leucocidinas/inmunología , Infecciones Estafilocócicas/prevención & control , Vacunas Estafilocócicas/efectos adversos , Vacunas Estafilocócicas/inmunología , Toxoides/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adolescente , Adulto , Compuestos de Alumbre/administración & dosificación , Anticuerpos Antibacterianos/sangre , Anticuerpos Neutralizantes/sangre , Toxinas Bacterianas/genética , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Exotoxinas/genética , Femenino , Voluntarios Sanos , Proteínas Hemolisinas/genética , Humanos , Inmunoglobulina G/sangre , Leucocidinas/genética , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Vacunas Estafilocócicas/administración & dosificación , Vacunas Estafilocócicas/genética , Toxoides/genética , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Adulto JovenRESUMEN
The attempted synthesis of a ring-expanded guanosine (1) containing the imidazo[4,5-e][1,3]diazepine ring system by condensation of 1-(2'-deoxy-beta-D-erythropentofuranosyl)-4-ethoxycarbonylimidazole-5-carbaldehyde (2) with guanidine resulted in the formation of an unexpected product, 1-(2'-deoxy-beta-D-erythropentofuranosyl)-5-(2, 4-diamino-3, 6-dihydro-1,3, 5-triazin-6-yl)imidazole-4-carboxamide (7). The structure as well as the pathway of formation of 7 was corroborated by isolation of the intermediate, followed by its conversion to the product. Nucleoside 7 showed promising in vitro anti-helicase activity against the West Nile virus NTPase/helicase with an IC50 of 3-10 microg/mL.
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Antivirales/síntesis química , Imidazoles/química , ARN Helicasas/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Virus del Nilo Occidental/enzimología , Antivirales/química , Relación Dosis-Respuesta a Droga , Guanosina/análogos & derivados , Guanosina/química , Imidazoles/síntesis química , Nucleósido-Trifosfatasa/antagonistas & inhibidores , Nucleósido-Trifosfatasa/química , ARN Helicasas/química , Proteínas Virales/químicaRESUMEN
In a previous study in end-stage renal disease (ESRD) hemodialysis patients, a single dose of Staphylococcus aureus type 5 and 8 capsular polysaccharides (T5/T8) conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A investigational vaccine showed no efficacy against S. aureus bacteremia 1 year post-vaccination, but a trend for efficacy was observed over the first 40 weeks post-vaccination. Vaccine efficacy (VE) of 2 vaccine doses was therefore evaluated. In a double-blind trial 3359 ESRD patients were randomized (1:1) to receive vaccine or placebo at week 0 and 35. VE in preventing S. aureus bacteremia was assessed between 3-35 weeks and 3-60 weeks post-dose-1. Anti-T5 and anti-T8 antibodies were measured. Serious adverse events (SAEs) were recorded for 42 days post-vaccination and deaths until study end. No significant difference in the incidence of S. aureus bacteremia was observed between vaccine and placebo groups between weeks 3-35 weeks post-dose 1 (VE -23%, 95%CI: -98;23, p = 0.39) or at 3-60 weeks post-dose-1 (VE -8%, 95%CI: -57;26, p = 0.70). Day 42 geometric mean antibody concentrations were 272.4 µg/ml and 242.0 µg/ml (T5 and T8, respectively) in vaccinees. SAEs were reported by 24%/25.3% of vaccinees/placebo recipients. These data do not show a protective effect of either 1 or 2 vaccine doses against S. aureus bacteremia in ESRD patients. The vaccine induced a robust immune response and had an acceptable safety profile. Further investigation suggested possible suboptimal vaccine quality (manufacturing) and a need to expand the antigen composition of the vaccine. This study is registered at www.clinicaltrials.gov NCT00071214.
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Bacteriemia/prevención & control , Diálisis Renal/efectos adversos , Infecciones Estafilocócicas/prevención & control , Vacunas Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antibacterianos/sangre , Bacteriemia/inmunología , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Incidencia , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Estudios Prospectivos , Infecciones Estafilocócicas/inmunología , Vacunas Estafilocócicas/administración & dosificación , Vacunas Estafilocócicas/efectos adversos , Resultado del Tratamiento , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/inmunología , Adulto JovenRESUMEN
Respiratory Syncytial Virus is a leading cause of bronchiolitis and pneumonia in infants, the elderly and individuals with compromised immune systems. Despite decades of research, there is currently no available vaccine for RSV. Our group has previously demonstrated that intranasal immunization of mice with RSV inactivated by and adjuvanted with W805EC nanoemulsion elicits robust humoral and cellular immune responses, resulting in protection against RSV infection. This protection was achieved without the induction of airway hyper-reactivity or a Th2-skewed immune response. The cotton rat Sigmodon hispidus has been used for years as an excellent small animal model of RSV disease. Thus, we extended these rodent studies to the more permissive cotton rat model. Intranasal immunization of the nanoemulsion-adjuvanted RSV vaccines induced high antibody titers and a robust Th1-skewed cellular response. Importantly, vaccination provided sterilizing cross-protective immunity against a heterologous RSV challenge and did not induce marked or severe histological effects or eosinophilia in the lung after viral challenge. Overall, these data demonstrate that nanoemulsion-formulated whole RSV vaccines are both safe and effective for immunization in multiple animal models.
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Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Emulsiones/uso terapéutico , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/uso terapéutico , Sigmodontinae/inmunología , Vacunas de Productos Inactivados/inmunología , Administración Intranasal , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Bronquiolitis/inmunología , Bronquiolitis/prevención & control , Bronquiolitis/virología , Protección Cruzada/inmunología , Femenino , Pulmón/patología , Pulmón/virología , Neumonía Viral/inmunología , Neumonía Viral/prevención & control , Neumonía Viral/virología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Sigmodontinae/virología , Células TH1/inmunología , Vacunación , Proteínas Virales de Fusión/inmunología , Carga Viral/inmunologíaRESUMEN
BACKGROUND: Staphylococcus aureus, the first or second most common pathogen isolated from patients, is capsulated; there are at least 12 capsular types, and types 5 and 8 comprise approximately 85% of blood. Types 5 and 8, composed of a trisaccharide repeat unit including a mannose uronic acid and 2 fucoses, are non-immunogenic. As protein conjugates, they induce opsonophagocytic antibodies that confer type-specific active and passive protection in mice. METHODS: A phase II study of patients with end-stage renal disease showed that these conjugates induced approximately one third of the immunoglobulin G antibody of healthy individuals. Increasing the dose to 100 microg of polysaccharide induced levels similar to that in healthy individuals injected with 25 microg. RESULTS: In a double-blinded randomized and controlled study of patients undergoing renal dialysis, the conjugates induced statistically significant protection against bacteremia for as long as 10 months after immunization. The estimated protective level was 80 microg Ab/mL. At re-injection approximately 2 years later, 83 of 83 recipients responded with protective levels. CONCLUSIONS: Conjugate vaccine-induced antibodies to the types 5 and 8 capsular polysaccharide antibodies of S aureus prevent bacteremia caused by this pathogen. The extent and duration of conjugate-induced immunity can be extended by re-immunization approximately 1 year later. Studies of patients undergoing cardiovascular surgery who would be immunized with the staphylococcus conjugates when they are immunologically intact are planned.
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Bacteriemia/prevención & control , Diálisis Renal , Infecciones Estafilocócicas/prevención & control , Vacunas Estafilocócicas , Staphylococcus aureus/inmunología , Adulto , Procedimientos Quirúrgicos Cardiovasculares , Método Doble Ciego , Humanos , Polisacáridos Bacterianos , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/clasificación , Staphylococcus aureus/patogenicidad , Vacunas ConjugadasRESUMEN
A series of ring-expanded ("fat") heterocycles, nucleoside and nucleotide analogues (RENs) containing the imidazo[4,5-e][1,3]diazepine ring system (9, 14, 15, 18, 24-26, 28, 31, and 33) and imidazo[4,5-e][1,2,4]triazepine ring systems (30b, 30c, 32, and 34), have been synthesized as potential inhibitors of NTPases/helicases of Flaviviridae, including the West Nile virus (WNV), hepatitis C virus (HCV), and Japanese encephalitis virus (JEV). An amino-terminal truncated form of human enzyme Suv3(delta1-159) was also included in the study so as to assess the selectivity of RENs against the viral enzymes. The analogues of RENs included structural variations at position 1 of the heterocyclic base and contained changes in both the type of sugar moieties (ribo, 2'-deoxyribo, and acyclic sugars) and the mode of attachment (alpha versus beta anomeric configuration) of those sugars to the heterocyclic base. The target RENs were biochemically screened separately against the helicase and ATPase activities of the viral NTPases/helicases. A number of RENs inhibited the viral helicase activity with IC50 values that ranged in micromolar concentrations and exhibited differential selectivity between the viral enzymes. In view of the observed tight complex between some nucleosides and RNA and/or DNA substrates of a helicase, the mechanism of action of RENs might involve their interaction with the appropriate substrate through binding to the major or minor groove of the double helix. The REN-5'-triphosphates, on the other hand, did not influence the above unwinding reaction, but instead exerted the inhibitory effect on the ATPase activity of the enzymes. The activity was found to be highly dependent upon the low concentration levels of the substrate ATP. At concentrations >500 microM of RENs and the ATP concentrations >10 times the Km value of the enzyme, a significant activation of NTPase activity was observed. This activating effect underwent further dramatic enhancement (>1000%) by further increases in ATP concentration in the reaction mixture. A tentative mechanistic model has been proposed to explain the observed results, which includes an additional allosteric binding site on the viral NTPases/helicases that can be occupied by nucleoside/nucleotide-type molecules such as RENs.
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Adenosina Trifosfatasas/antagonistas & inhibidores , ADN Helicasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Flaviviridae/enzimología , Nucleósidos/química , Nucleósidos/farmacología , Nucleótidos/química , Nucleótidos/farmacología , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/metabolismo , Azepinas/química , Azepinas/farmacología , ADN/metabolismo , ADN Helicasas/química , Virus de la Encefalitis Japonesa (Especie)/enzimología , Hepacivirus/enzimología , Humanos , Concentración 50 Inhibidora , Nucleósidos/síntesis química , Nucleótidos/síntesis química , Poliproteínas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Virus del Nilo Occidental/enzimologíaRESUMEN
A series of ring-expanded ("fat") nucleoside analogues (RENs) containing the 6-aminoimidazo[4,5-e][1,3]diazepine-4,8-dione ring system have been synthesized and screened for inhibition of NTPase/helicase of the West Nile Virus (WNV). To assess the selectivity of RENs against the viral enzymes, a truncated form of human enzyme Suv3((Delta)(1)(-)(159)) was also included in the study. Ring-expanded nucleosides 16, 17, and 19, which possess the long C(12), C(14), and C(18) side-chains, respectively, at position 6, as well as the ring-expanded heterocycle 39, which contains aralkyl substitution at position 1, were all found to have excellent profiles of activity and selectivity toward the viral versus human enzymes against the West Nile Virus (IC(50) ranging 1-10 muM). Compound 30, while being an equally potent inhibitor of WNV, was found to be somewhat less selective, whereas compound 36, which is an alpha-anomeric counterpart of 30, exhibited potent and selective inhibition of WNV (IC(50) 1-3 muM). The same compounds that showed potent inhibition of viral helicase activity completely failed to show any activity against the viral NTPase reaction even up to 500 muM. However, at concentrations >500 muM of RENs and the ATP concentrations >10 times the K(m) value of the enzyme, a significant activation of NTPase activity was observed. This activating effect underwent further dramatic enhancement (>1000%) by further increases in ATP concentration in the reaction mixture, suggesting that the viral helicase and NTPase reactions are not coupled. A tentative mechanistic model has been proposed to explain the observed results.