ABSTRACT
Introducción: La vacuna antialérgica de segunda generación PROLINEM-DS está compuesta por alérgenos del ácaro Dermatophagoides siboney y la combinación de adyuvantes: proteoliposoma de N. meningitidis B y gel de hidróxido de aluminio. La adsorción del alérgeno es relevante para la seguridad y eficacia clínica de las vacunas adsorbidas en gel de hidróxido de aluminio en estudios previos se demostró la influencia negativa de los iones fosfato en la adsorción del alérgeno. Objetivo: Evaluar la inmunogenicidad y capacidad protectora de cuatro variantes de formulación obtenidas dentro del espacio de diseño de la vacuna PROLINEM DS. Métodos: Se emplearon 4 variantes de formulación con diferentes contenidos de tampón fosfato salino y gel de hidróxido de aluminio. Se administraron a ratones BALB/c 3 dosis subcutáneas una por semana. Luego, los ratones fueron sometidos a reto alergénico por aerosol. Resultados: Todas las variantes indujeron anticuerpos IgG1 e IgG2a alérgeno específico. Este efecto se correlacionó con el balance de citoquinas proinflamatorias Th1/Th2 en los pulmones y en los ganglios. La variante con reducción de tampón fosfato salino y gel de hidróxido de aluminio fue la de mayor índice IgG/IgE después de la vacunación. Esta relación muestra, en una variable, el equilibrio entre los componentes potencialmente bloqueadores y efectores. La tolerancia local en el lugar de la inyección mostró una reducción de los granulomas en los ratones vacunados con menos gel de hidróxido de aluminio. Conclusiones: La reducción del contenido de gel de hidróxido de aluminio y fosfatos se consideran mejoras farmacéuticas sin inconvenientes en cuanto a la inmunogenicidad de esta vacuna con un perfil de seguridad satisfactorio para futuros ensayos clínicos en humanos.
Introduction: The second generation anti allergic vaccine named PROLINEM DS is based on allergens from D. siboney house dust mite and a combination adjuvant containing PL and Alum. Allergen adsorption is relevant both safety and clinical efficacy in alum-adsorbed vaccines. Negative influence of phosphate ions on allergen adsorption was demonstrated in previous researches. Objective: To evaluate immunogenicity and protective efficacy of four variants obtained within design space of PROLINEM DS vaccine. Methods: Four variants were differentiated from each other by both phosphate and alum contents. Balb/c mice were administered with 3 doses by subcutaneous route. Further, mice were subjected to allergen aerosol challenge. Results: Specific IgG1 and IgG2a antibodies were induced by four vaccine variants. It was correlated with pro inflammatory cytokines balance Th1/Th2 both in lungs and lymphatic nodes. Formulation with lower PBS and Alum levels showed the highest IgG/IgE ratio at the end of vaccination schedule. This ratio shows in one variable the balance between potentially blocking and effector components. Mice injected with lower level of Alum showed a reduction of granuloma size in the site of vaccine administration. Conclusion: Decrease both alum and phosphate contents were a pharmaceutical improvement for antiallergic vaccines formulation. Safety and efficacy in this vaccine are crucial for future human clinical trials.
Subject(s)
HumansABSTRACT
BACKGROUND: Sensitization to Blomia tropicalis (Bt) is very frequent in the tropics, and particularly in Cuba, being a significant cause of allergic asthma. Allergen immunotherapy (AIT) with Bt can be a therapeutic option, however, placebo-controlled clinical trials have not been reported. OBJECTIVE: To assess the therapeutic effect and safety of AIT for asthma using a standardized allergen vaccine of B. tropicalis by subcutaneous route, in allergic asthmatic patients exposed and sensitized to this mite species. METHODS: A double-blind, placebo-controlled Phase II trial was conducted in 35 adults (18 with treatment and 17 with placebo), with mild to moderate asthma, predominantly sensitized to Bt. AIT was administered subcutaneously in increasing doses from 4 to 6000 Biological Units using a locally manufactured standardized extract (BIOCEN, Cuba). Patient assessment was performed using symptom-medication score (SMS), peak expiratory flow and skin reactivity relative to Histamine as measured by skin prick test (SPT). RESULTS: The 12-month treatment achieved a significant (p < 0.001) decrease of SMS. Symptom score showed only 41% (CI: 26-61) of placebo values, whereas medication was 34.5% (22.4%-63.3%). Treatment was regarded clinically effective in 67% of patients (OR 32; 95%CI: 17 to 102). The effect size on symptoms and medication was higher than has been reported with equivalent allergen dosages of D. pteronyssinus and D. siboney in Cuban asthmatic patients. Skin reactivity to Bt was also significantly reduced (p = 0.0001), increasing 148-fold the allergen threshold to elicit a positive skin test. This desensitization effect was specific to Bt and did not modify the reactivity to Dermatophagoides. The change of specific skin reactivity was significantly (p < 0.05) correlated to clinical improvement. All adverse events were local with a frequency of 2.4% of injections. CONCLUSIONS: Subcutaneous AIT with Blomia tropicalis was effective and safe in asthmatic adults exposed and sensitized to this mite species in a tropical environment. TRIAL REGISTRATION: Cuban Public Registry of Clinical Trials: RPCEC00000026 (WHO International Clinical Trial Registry Platform ICTRP).
ABSTRACT
New adjuvant formulations, based on proteoliposomes <40â¯nm and cochleates <100â¯nm, without Al(OH)3 adjuvant, were evaluated regarding their ability to generate Th1 immune response through a Delayed -Type Hypersensitivity Test, at the mouse model, by using a Neisseria meningitidis B protein complex as antigen. The formulations were administered by intramuscular (IM) (2 inoculations - at baseline and after 14â¯days) and intranasal (IN) (3 inoculations at 7â¯days) immunization pathways. All IM immunized groups were able to induce similar response to these formulations as well as to VA-MENGOC-BC® vaccine - containing Al(OH)3 adjuvant (used as positive control of the trial). In all groups, the induced inflammation (IP) rate was statistically higher than in the negative control group (CN) (pâ¯<â¯0.05). Immunogenicity, measured by HSR and CD4+ lymphocyte increase was equivalent to the control vaccine and most important, granuloma reactogenicity at the site of injection was eliminated, fact demonstrated by histological study. All groups of animals immunized by IN route showed HSR reactions and statistically significant differences with respect to the CN group. However, IP values were lower, with statistical differences (pâ¯<â¯0.05) for the same adjuvant formulation IM administered, except the AIF2-nCh formulation that generated statistically similar induction (pâ¯>â¯0.05) by both immunization pathways, suggesting it to be the best candidate for the next IN trial. Proteoliposome and cochleate formulations tested were able to mount potent Th-1 immune response, equivalent to the original vaccine formulation, with the advantage of less reactogenicity in the site of the injection, caused by the toxicity of Al(OH)3 adjuvant gel.
