RESUMEN
Epidermal powder immunization (EPI) of mice with an influenza vaccine elicited consistently a higher hemagglutination inhibition (HI) antibody titers than intramuscular (IM) injection using the same dose of vaccine. The epidermal Langerhans cells (LCs) at the site of EPI were found to play an important role in the immune responses. Indeed, depletion of LCs from the immunization site prior to EPI caused a significant reduction in the antibody response. Transfer of LCs isolated from the EPI sites to naive mice induced a robust antigen-specific antibody response. Cytokines produced by target site cells appear to be important for the augmented immune responses induced by EPI. LTR72, a genetically detoxified heat-labile toxin from Escherichia coli with a strong adjuvant effect in EPI, was found to bind the keratinocytes of the epidermis, but not the LCs, and caused the production of elevated TNF-alpha and IL-12 cytokines in emigrating epidermal cells. These results have important implications for the development of a more efficacious human influenza vaccine.
Asunto(s)
Citocinas/inmunología , Epidermis/inmunología , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Células de Langerhans/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Adyuvantes Inmunológicos/administración & dosificación , Animales , Anticuerpos Antivirales/sangre , Citocinas/metabolismo , Células Epidérmicas , Femenino , Pruebas de Inhibición de Hemaglutinación , Inmunización/métodos , Virus de la Influenza A/inmunología , Virus de la Influenza B/inmunología , Inyecciones Intramusculares , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/inmunología , Polvos/administración & dosificaciónRESUMEN
The non-toxic B subunit of cholera toxin (CTB) and E. coli heat-labile toxin mutant proteins with reduced toxicity (LTR72) or no toxicity (LTK63) were used as adjuvants for epidermal powder immunization (EPI) with an influenza vaccine. When administered by EPI, CTB, LTR72 and LTK63 significantly augmented antibody responses to the influenza vaccine and protection against a lethal challenge in a mouse model. The antigen dose could be reduced by 125-fold. These adjuvants were well-tolerated both locally and systemically following EPI. These results suggest that EPI with influenza vaccine and a non-toxic bacterial enterotoxin hold promise for human vaccination.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Anticuerpos Antivirales/sangre , Antígenos Bacterianos/inmunología , Toxinas Bacterianas/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/genética , Administración Cutánea , Animales , Toxinas Bacterianas/genética , Hemaglutininas Virales/inmunología , Inmunidad Mucosa , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Ratones , Modelos Animales , Infecciones por Orthomyxoviridae/inmunología , Polvos , Seguridad , VacunaciónRESUMEN
Epidermal powder immunization (EPI) with an influenza vaccine and an adjuvant such as QS-21, LTR72, or cholera toxin elicited augmented serum and mucosal antibody responses in mice. Rhesus macaques, which have an immune system and skin structure similar to humans, were used to further evaluate the immunogenicity of the influenza vaccine following EPI. EPI of rhesus macaques with an influenza vaccine and QS-21 adjuvant elicited significantly higher serum hemagglutination inhibition (HI) titers than antigen alone administered by EPI or by intramuscular (IM) injection using a needle and syringe. In the absence of QS-21, EPI and IM injection elicited comparable HI titers in the monkeys. This study suggests that EPI is a promising technique for administering human vaccine and that QS-21 augments the immunogenicity of co-administered influenza vaccine.