RESUMEN
The specificity of viral antigens in the formalin-inactivated, alum-precipitated respiratory syncytial virus (FI-RSV) vaccine in augmenting the pulmonary inflammatory response was evaluated. Cotton rats were immunized with a FI-RSV vaccine derived from Vero cells, a monkey cell line, or HEp-2 cells, a human cell line. The FI-RSV/Vero and the FI-RSV/HEp-2 vaccines were prepared similarly to the original Lot-100 FI-RSV vaccine that was associated with enhanced disease in the mid-1960s field trials. Each vaccine was administered intramuscularly at various doses and intervals. At 1, 4 or 7 weeks after the last vaccine dose, cotton rats were challenged with 10(6) plaque-forming units of live RSV grown in HEp-2 cells. For controls, FI-parainfluenza, FI-HEp-2 and alum vaccines, and live RSV primary infection were used. For measuring virus replication and histopathology, lungs were harvested at 4 and 8 days postchallenge. A dose-response relationship to vaccine dose was observed for ELISA, neutralizing and antifusion antibodies. All animals given three doses or two of the higher doses of FI-RSV/Vero vaccine developed significant neutralizing antibody, were protected against pulmonary virus replication and had similar low levels of histopathology compared with live RSV and controls. Two immunizations of the lowest dose of FI-RSV/Vero vaccine did not induce neutralizing antibody, did not provide protection of the lung against RSV and did not enhance the pulmonary cellular response. However, FI-RSV/HEp-2 vaccine was associated with significant enhanced pulmonary histopathology despite inducing high titres of neutralizing antibody and protecting the lungs against RSV infection.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Formaldehído/efectos adversos , Pulmón/efectos de los fármacos , Pulmón/patología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitial Respiratorio Humano/inmunología , Vacunas de Productos Inactivados/efectos adversos , Vacunas Virales/efectos adversos , Animales , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Antígenos Virales/inmunología , Chlorocebus aethiops , Epítopos , Humanos , Inmunización , Lactante , Pulmón/microbiología , Ratas , Infecciones por Virus Sincitial Respiratorio/patología , Virus Sincitial Respiratorio Humano/fisiología , Sigmodontinae , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
SP-303, a naturally occurring polyphenolic polymer (average M.W. = 2100 Da), was tested in cotton rats (Sigmoden hispidus) for antiviral activity against respiratory syncytial (RSV) and parainfluenza type 3 (PIV3) viruses, and for acute toxicity. Significant reductions in pulmonary RSV titers, compared to pulmonary RSV titers in comparably treated control animals, were seen in cotton rats given 1-10 mg SP-303/kg/day intraperitoneally (i.p.) on days 1 through to 3, after experimental inoculation with RSV. The minimum efficacious dose of SP-303 against PIV3, when given i.p. for 3 days, was 3 mg/kg/day. Higher doses of SP-303 could not be given i.p., as doses > or = 30 mg/kg/day given once daily by this route for 3 or more consecutive days caused both significant weight loss and death in infected or uninfected animals. Although no toxicity was observed following oral administration of up to 270 mg of SP-303 daily for 3 days, this compound had variable antiviral activity when given by this route.
Asunto(s)
Antivirales/uso terapéutico , Biopolímeros/farmacología , Catequina/análogos & derivados , Virus de la Parainfluenza 3 Humana/efectos de los fármacos , Infecciones por Paramyxoviridae/prevención & control , Virus Sincitiales Respiratorios/efectos de los fármacos , Infecciones por Respirovirus/prevención & control , Animales , Antivirales/administración & dosificación , Peso Corporal , Catequina/farmacología , Técnicas de Cultivo , Pulmón/microbiología , Pulmón/patología , Infecciones por Paramyxoviridae/microbiología , Plantas Medicinales/química , Infecciones por Respirovirus/microbiología , Ribavirina/farmacología , Sigmodontinae , Ensayo de Placa ViralRESUMEN
Virus-specific, T-lymphocyte-mediated delayed type hypersensitivity (DTH) responses were studied in cotton rats using replicating (wild-type parainfluenza virus type 3 (PIV3) and recombinant vaccinia virus expressing PIV3 haemagglutinin-neuraminidase (HN) or fusion (F) glycoproteins), and non-replicating (detergent-solubilized, affinity chromatography purified HN and F glycoproteins or inactivated whole PIV3) virus preparations. Significant virus-specific DTH responses were observed in all test groups 1-2 weeks after a single antigen inoculation or 5 days after two inoculations given 3 weeks apart. Peak swelling of ear pinnas in these animals generally occurred 24 h after elicitation and was marked by a cellular infiltration consisting of mono- and polymorphonuclear leucocytes. A considerable non-virus-specific inflammatory response, presumably due to tissue culture or media components in the priming antigen preparations, was observed 3 weeks after priming. No significant differences in DTH responses were observed in cotton rats primed with any of the PIV3 preparations. The possible roles and significance of both the virus-specific and non-virus-specific DTH responses in paramyxovirus-induced disease in humans and cotton rats are discussed.
Asunto(s)
Antígenos Virales/administración & dosificación , Hipersensibilidad Tardía , Virus de la Parainfluenza 3 Humana/inmunología , Animales , Antígenos Virales/aislamiento & purificación , Humanos , Hipersensibilidad Tardía/patología , Inmunización Pasiva , Cinética , Virus de la Parainfluenza 3 Humana/genética , Virus de la Parainfluenza 3 Humana/fisiología , Sigmodontinae , Vacunas de Productos Inactivados/administración & dosificación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/aislamiento & purificación , Vacunas Virales/administración & dosificación , Vacunas Virales/aislamiento & purificación , Replicación ViralRESUMEN
Hispid cotton rats were inoculated intranasally with either measles virus (MV) Edmonston, a multipassaged, tissue culture-adapted strain of MV, or with one of three clinical MV isolates that had limited passages (three to five times) in tissue culture cells. MV Edmonston was recovered from the lungs of every (n = 37) hispid cotton rat inoculated with this virus for at least 7 days after virus inoculation. Peak pulmonary titers occurred on Day +4 (3.3-4.4 log10/g lung). Scattered areas of inflammation were observed interstitially in lung sections from infected animals stained with hematoxylin and eosin, and a similar pattern of diffuse fluorescence was seen in cryostat sections stained with an indirect fluorescent antibody procedure specific for virus antigens. Fluorescent antibody and virus isolation studies on lung lavage cells both suggested that lung leukocytes were a primary target of the virus. In contrast to these findings, virus was isolated only sporadically from hispid cotton rats inoculated with any of the clinical measles virus isolates. Despite the restricted growth of MV in these animals, cotton rats may be useful for studying certain aspects of measles virus pathogenesis and for screening potential antiviral compounds in vivo.
Asunto(s)
Pulmón/microbiología , Virus del Sarampión/patogenicidad , Administración Intranasal , Animales , Anticuerpos Antivirales/biosíntesis , Modelos Animales de Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente , Pulmón/patología , Masculino , Ratas , Factores de Tiempo , Replicación ViralRESUMEN
Ribavirin aerosol administration has been shown to be effective in the treatment of respiratory syncytial virus (RSV) infections in infants and in influenza A and B virus infections in young adults. Long treatment schedules and potential for environmental contamination have stimulated the search for alternative dosing schedules. Thus, we attempted to determine the length of time of ribavirin aerosol necessary for effective treatment of influenza and RSV. In RSV-infected cotton rats, aerosolization for just 30 min with high-dose ribavirin (HDR:60 mg ribavirin/ml in reservoir), 3 times daily, reduced viral lung titers/gm of tissue by 1.1 log10. In influenza virus-infected mice, 15 min of aerosolized HDR, 3 times daily, was effective in reducing both mortality and pulmonary virus titers (1.1 log10 reduction). When the intervals between aerosol administration each day were equally divided (i.e., q.8 h), the treatments were most effective. Treatment for 45 min, once daily, was not as effective as divided doses. Calculations of ribavirin concentrations in respiratory secretions following 15 min treatment in mice with HDR indicated that drug levels dropped below the ED50 for influenza viruses after about 9 h. A daily dosage of ribavirin, estimated to be 8-15 mg/kg, was effective for the treatment of influenza and RSV infections.
Asunto(s)
Virus de la Influenza A/efectos de los fármacos , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Virus Sincitiales Respiratorios/efectos de los fármacos , Infecciones por Respirovirus/tratamiento farmacológico , Ribavirina/uso terapéutico , Aerosoles , Animales , Línea Celular , Perros , Esquema de Medicación , Ratones , Sigmodontinae , Factores de TiempoRESUMEN
A parainfluenza virus type 3 (PIV3) subunit vaccine consisting of detergent-solubilized, affinity-purified haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins was tested in cotton rats for immunogenicity, short-term effects on virus-induced immunopathology and protective efficacy. Groups of animals were immunized twice, 4 weeks apart, with graded doses of vaccine administered either alone or with aluminium phosphate (AlPO4). The minimum immunogenic dose of vaccine was 0.1 microgram HN and F when the vaccine was given alone and 0.01 microgram when the vaccine was administered with AlPO4 adjuvant. Antibody responses in animals immunized with 1 microgram HN and F mixed with adjuvant were similar to those in control animals infected with live PIV3 intranasally. Pulmonary and nasal wash PIV3 titres generally were inversely correlated with serum antibody levels. Virus titres were significantly reduced in all groups of animals immunized with greater than or equal to 0.1 microgram HN and F compared with control animals immunized with vehicle only. Four days after virus challenge, there was no evidence of enhanced histopathology in lung sections from animals immunized with the candidate vaccine.
Asunto(s)
Compuestos de Aluminio , Anticuerpos Antivirales/sangre , Virus de la Parainfluenza 3 Humana/inmunología , Infecciones por Paramyxoviridae/prevención & control , Vacunas Virales/inmunología , Adyuvantes Inmunológicos , Aluminio/inmunología , Animales , Línea Celular , Femenino , Proteína HN/inmunología , Pruebas de Hemaglutinación , Pulmón/microbiología , Masculino , Pruebas de Neutralización , Virus de la Parainfluenza 3 Humana/aislamiento & purificación , Fosfatos/inmunología , Sigmodontinae , Proteínas Virales de Fusión/inmunología , Vacunas Virales/administración & dosificación , Vacunas Virales/efectos adversosRESUMEN
The toxicity and antiviral efficacy of carbocyclic 3-deazaadenosine (Cc3Ado) against respiratory syncytial (RSV) and parainfluenza type 3 (PIV3) virus infections were tested in tissue culture and in cotton rats. The mean median efficacious dose (ED50) of Cc3Ado in HEp2 cells against RSV and PIV3 was 9 and 14 micrograms/ml, respectively. These values were 85- and 55-fold less than the median inhibitory (toxic) dose (ID50) of Cc3Ado in this cell line (750 micrograms/ml), and similar to values obtained for ribavirin. Cc3Ado exhibited no significant antiviral activity against influenza A, influenza B, adeno type 5 or adeno type 7 viruses (all ED50 were greater than 1000 micrograms/ml). In cotton rats, animals given greater than or equal to 1 mg/kg/day Cc3Ado intraperitoneally on days 1, 2 and 3 after experimental challenge with virus, consistently had significant reductions in pulmonary RSV and PIV3 titers compared to pulmonary virus titers in comparably treated control animals. The minimum efficacious dose of ribavirin given under the same conditions was 30 mg/kg/day. Cc3Ado was also efficacious in cotton rats when given orally by gavage, or when different administration schedules were used. The median efficacious dose of Cc3Ado when given orally was 10 mg/kg/day. No significant toxic effects were noted in cotton rats, even in animals given 20 mg/kg daily for eight consecutive days.
Asunto(s)
Antivirales/toxicidad , Virus de la Parainfluenza 3 Humana/efectos de los fármacos , Virus Sincitiales Respiratorios/efectos de los fármacos , Tubercidina/análogos & derivados , Replicación Viral/efectos de los fármacos , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Virus de la Parainfluenza 3 Humana/crecimiento & desarrollo , Infecciones por Paramyxoviridae/tratamiento farmacológico , Infecciones por Paramyxoviridae/patología , Ratas , Virus Sincitiales Respiratorios/crecimiento & desarrollo , Infecciones por Respirovirus/tratamiento farmacológico , Infecciones por Respirovirus/patología , Tubercidina/farmacología , Tubercidina/toxicidadRESUMEN
LY253963, the sodium salt of 1,3,4-thiadiazol-2-ylcyanamide, was evaluated in tissue culture and in cotton rats for toxicity and antiviral efficacy against respiratory syncytial (RSV) and parainfluenza type 3 (PIV3) viruses. The selective index (ratio of the median toxic dose: median efficacious dose) of LY253963 in HEp2 tissue culture cells was greater than 100 against both RSV and PIV3. When given intraperitoneally to cotton rats, the minimum protective dose of LY253963 against both of these viruses was between 1 and 3 mg/kg/day. In contrast, doses of LY253963 as high as 30 mg/kg/day, administered orally after experimental inoculation of virus, did not significantly reduce pulmonary virus titers in treated animals compared to control animals given placebo. No toxic effects were noted in cotton rats, even in those given 20 mg/kg/day for eight consecutive days.
Asunto(s)
Antivirales/farmacología , Nitrilos/farmacología , Infecciones por Paramyxoviridae/tratamiento farmacológico , Virus Sincitiales Respiratorios/efectos de los fármacos , Infecciones por Respirovirus/tratamiento farmacológico , Respirovirus/efectos de los fármacos , Tiadiazoles/farmacología , Animales , Antivirales/administración & dosificación , Línea Celular , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Infecciones por Paramyxoviridae/patología , Ratas , Infecciones por Respirovirus/patología , Ribavirina/administración & dosificación , Ribavirina/farmacologíaRESUMEN
Muramyl dipeptide (MDP), murabutide (a derivative of MDP), mouse alpha-interferon (MoIFN), and polyinosinic-polycytodylic acid (poly (I-C) were tested in a mouse-influenza virus model for anti-influenza virus activity. None of these compounds administered alone prior to virus challenge had more than minimal ability to protect mice from influenza virus infection. In contrast, mice given either MDP or murabutide 2 days prior to challenge with influenza A/Hong Kong/68 virus and poly I-C 1 day prior to virus challenge had significantly reduced pulmonary virus titers and mortality compared to comparably challenged control mice. No significant reductions in pulmonary virus titers or mortality were seen if MoIFN was given in place of poly I-C in this sequence.
Asunto(s)
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Acetilmuramil-Alanil-Isoglutamina/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , Infecciones por Orthomyxoviridae/prevención & control , Poli I-C/uso terapéutico , Animales , Quimioterapia Combinada , Interferón Tipo I/uso terapéutico , Pulmón/metabolismo , Masculino , RatonesRESUMEN
The effects of influenza A/Hong Kong/68 (H3N2) virus infection on clearance of bacteria (Staphylococcus aureus or Serratia marcescens) from lungs of young adult (8-week-old) and aged (2-year-old) CBA/2N mice were studied. No consistent differences in pulmonary bacterial clearance were observed in uninfected animals of either age group. However, both young and aged virus-infected mice consistently exhibited significantly reduced ability to clear challenge bacteria from their lungs compared to age-matched nonvirus-infected controls; this deficit was markedly more pronounced in virus-infected aged mice. The extra deficit seen in virus-infected aged animals did not correlate with pulmonary virus or interferon titers, or with severity of pulmonary histopathology. Moreover, the phagocytic and bactericidal activities of pulmonary macrophages and polymorphonuclear neutrophiles from virus-infected young and aged mice were comparable.
Asunto(s)
Envejecimiento/fisiología , Bacterias/crecimiento & desarrollo , Pulmón/microbiología , Infecciones por Orthomyxoviridae/microbiología , Animales , Técnicas de Cultivo , Virus de la Influenza A/aislamiento & purificación , Interferones/metabolismo , Pulmón/metabolismo , Pulmón/patología , Macrófagos/inmunología , Macrófagos/patología , Ratones , Ratones Endogámicos CBA , Neutrófilos/patología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/patología , Fagocitosis , Serratia marcescens/crecimiento & desarrollo , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
Based on reports describing their broad antiviral activity, the toxicity and antiviral efficacy of papaverine hydrochloride and pyrazofurin against respiratory syncytial virus (RSV) infection were tested in vitro in tissue culture cells and in vivo in cotton rats. Papaverine inhibited RSV replication in vitro; however, the median minimal toxic dose-median minimal inhibitory concentration ratios (MTD50:MIC50) in vitro and in vivo for papaverine were less than 4. Further work with this compound was discontinued. In contrast, pyrazofurin inhibited RSV replication in vitro (a mean MIC50 of 0.04 microgram/ml was obtained) and in vivo (RSV pulmonary titers were significantly reduced consistently in cotton rats given daily 10 mg/kg doses compared to untreated control animals). However, some toxic effects were observed in both the in vitro and in vivo tests of this compound. The remaining potential of pyrazofurin as an anti-RSV compound is discussed.