RESUMO
Measles vaccination via the aerosol route has proven effective under field conditions, using vaccine reconstituted prior to nebulization. Inhalation of a dry powder aerosol vaccine would have additional benefits, including easier logistics of administration, reduced cold chain dependence and the potential of single dose administration. We have evaluated two candidate dry powder measles vaccine formulations in macaques. Specific immune responses were demonstrated, but levels of immunity were lower than in animals vaccinated by injection or by nebulized aerosol. These studies provide proof of principle that dry powder inhalation is a possible route for measles vaccination, but suggest that either the vaccine formulation or the method of delivery need to be improved for a better immune response.
Assuntos
Vacina contra Sarampo/administração & dosagem , Vacina contra Sarampo/uso terapêutico , Administração por Inalação , Anestesia Endotraqueal , Animais , Anticorpos Antivirais/análise , Anticorpos Antivirais/biossíntese , Injeções , Pulmão/metabolismo , Macaca fascicularis , Sarampo/imunologia , Sarampo/prevenção & controle , Vírus do Sarampo/química , Testes de Neutralização , Tamanho da Partícula , Pós , RNA Viral/análise , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vacinação/métodos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/uso terapêuticoRESUMO
The comparative efficacy and safety of measles vaccination via the aerosol route versus subcutaneous injection has not been fully resolved. We vaccinated cynomolgus monkeys (Macaca fascicularis) with the live-attenuated Edmonston-Zagreb measles virus (MV) vaccine and compared different routes of administration in the immunocompetent and the immunocompromised host. Immunogenicity and protective efficacy of aerosol vaccination using devices similar to those previously used in humans were comparable to those in animals vaccinated by injection. No evidence for a safety hazard associated with the route of vaccination was detected. The results of this study support further clinical evaluation of aerosol vaccination for measles.
Assuntos
Vacina contra Sarampo/administração & dosagem , Vacina contra Sarampo/imunologia , Aerossóis/administração & dosagem , Animais , Formação de Anticorpos/imunologia , Células Cultivadas , Relação Dose-Resposta Imunológica , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Hospedeiro Imunocomprometido/imunologia , Macaca , Masculino , Sarampo/imunologia , Sarampo/virologia , Vacina contra Sarampo/efeitos adversos , Vírus do Sarampo/fisiologia , Replicação ViralRESUMO
Quil A-based candidate measles vaccines have been shown to be immunogenic and protective in cotton rats and macaques. Here we studied the longevity of protective VN antibody levels induced in macaques with one dose of measles virus (MV) iscom. Inactivated MV adjuvanted with iscom-matrix or with purified Quillaja saponin QA-22 were also tested. All animals developed high levels of VN antibody and MV-specific IFNgamma-producing cells. Especially the high VN antibody levels induced by the latter two preparations showed virtually no decrease during the 2-year follow-up. These highly promising candidate MV vaccines should now be tested in infant macaques in the presence or absence of passively transferred and/or maternally derived VN antibodies. In addition, the immunopathological safety of the constructs should be evaluated in the atypical measles model in rhesus macaques.
Assuntos
Anticorpos Antivirais/imunologia , Vacina contra Sarampo/imunologia , Saponinas/química , Adjuvantes Imunológicos/química , Animais , Anticorpos Antivirais/fisiologia , Ativação Linfocitária , Sarampo/imunologia , Sarampo/prevenção & controle , Vírus do Sarampo/imunologia , Saponinas de Quilaia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vaccinia virus , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/imunologiaRESUMO
Although the currently used live attenuated measles vaccines are safe and effective, they are dependent on cold chain maintenance and are often ineffective in young infants due to interference by maternal antibody. Therefore, besides vector-based vaccines, different new generation non-replicating candidate measles vaccines are being considered, including nucleic acid vaccines. We have vaccinated cynomolgus macaques transdermally with DNA plasmids encoding measles virus (MV) proteins. Following two vaccinations, low serum antibody responses were detected. Wild-type measles virus challenge 1 year after vaccination showed reduced viraemia in some animals. However, accelerated humoral- and cellular-immune responses were observed in all vaccinated macaques, demonstrating successful priming by the DNA vaccines.
Assuntos
Anticorpos Antivirais/sangue , Interferon gama/biossíntese , Vacina contra Sarampo/imunologia , Vacinas de DNA/imunologia , Animais , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Macaca fascicularis , VacinaçãoRESUMO
To test the option of oral vaccination with a live attenuated measles vaccine (LAV), we have evaluated the potential of an orally administered enteric-coated tablet containing a candidate LAV (strain Leningrad-16, MV-L16). To this end three groups of two cynomolgus macaques each were vaccinated via different routes with 10(3.8) TCID(50) MV-L16 vaccine: intramuscularly (i.m.), intraintestinally (i.i.) upon laparotomy and via enteric-coated tablets. Upon vaccination, MV-L16 could only be isolated from one of the i.m.-vaccinated monkeys and not from any of the other five. Both the i.m.-infected monkeys and one of the i.i.-infected monkeys developed a MV-specific serum antibody response. Also, MV-specific CD8(+) IFN gamma-producing T cells could be demonstrated in all three monkeys that had seroconverted. Upon challenge with wild-type MV 1 year after vaccination, only these three monkeys proved to be protected. These data do not support the viability of the concept of oral vaccination with LAVs.
Assuntos
Vacina contra Sarampo/administração & dosagem , Administração Oral , Animais , Anticorpos Antivirais/biossíntese , Humanos , Imunoglobulina M/sangue , Injeções , Injeções Intramusculares , Intestino Delgado , Macaca fascicularis , Sarampo/imunologia , Sarampo/prevenção & controle , Vírus do Sarampo/imunologia , Vírus do Sarampo/isolamento & purificação , Vírus do Sarampo/patogenicidade , Testes de Neutralização , Linfócitos T/imunologia , Comprimidos com Revestimento Entérico , Vacinas Atenuadas/administração & dosagemRESUMO
Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. RSV vaccine development has been hampered by results of clinical trials in the 1960s, when formalin-inactivated whole-RSV preparations adjuvated with alum (FI-RSV) were found to predispose infants for enhanced disease following subsequent natural RSV infection. We have reproduced this apparently immunopathological phenomenon in infant cynomolgus macaques and identified immunological and pathological correlates. Vaccination with FI-RSV induced specific virus-neutralizing antibody responses accompanied by strong lymphoproliferative responses. The vaccine-induced RSV-specific T cells predominantly produced the Th2 cytokines interleukin-13 (IL-13) and IL-5. Intratracheal challenge with a macaque-adapted wild-type RSV 3 months after the third vaccination elicited a hypersensitivity response associated with lung eosinophilia. The challenge resulted in a rapid boosting of IL-13-producing T cells in the FI-RSV-vaccinated animals but not in the FI-measles virus-vaccinated control animals. Two out of seven FI-RSV-vaccinated animals died 12 days after RSV challenge with pulmonary hyperinflation. Surprisingly, the lungs of these two animals did not show overt inflammatory lesions. However, upon vaccination the animals had shown the strongest lymphoproliferative responses associated with the most pronounced Th2 phenotype within their group. We hypothesize that an IL-13-associated asthma-like mechanism resulted in airway hyperreactivity in these animals. This nonhuman primate model will be an important tool to assess the safety of nonreplicating candidate RSV vaccines.