New adjuvant formulations, based on proteoliposomes <40 nm and cochleates <100 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 14 days) and intranasal (IN) (3 inoculations at 7 days) immunization pathways. All IM immunized groups were able to induce similar response to these formulations as well as to VA-MENGOC-BC® vaccinecontaining 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) (p<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 (p<0.05) for the same adjuvant formulation IM administered, except the AIF2-nCh formulation that generated statistically similar induction (p>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.

The proteoliposomes and cochleates are used as adjuvants for vaccines since they are potent immune stimulators. However, the hyper stimulation of the immune system provoked by adjuvants can cause immune-toxicological side effects. The present study was carried out to evaluate the toxic and immuno-toxicological effects of new adjuvants for anti-meningococci vaccines based on neo-proteoliposomes (nPL) and neo-cochleates (nCh), in Balb/c mice that were administered doses of 15 �g each, over periods of 14 days through intramuscular route and three inoculations with the same doses through intranasal route, every 7 days. The Scanning and Transmission Electron Microscopy showed that the nPL and nCh had nanometric dimensions and their normal peculiar forms. The experimental formulations did not provoke general toxic effects in the tested animals, which tended to the progressive normal growing of this species, that did not statistically differ from the control ones. The studies of pathologic anatomy in inoculation organs and sites did not reveal modifications that can indicate toxicity and there was no sign of hepatic damage. The structural observations found in the spleen and lymphatic nodes showed the physiological development of the immune response, which was normal in all cases showing the restitution of the stimulation signs. The relative weight values of the spleen were within the standard range. These results showed that the nPL and nCh elaborated as adjuvants for vaccines did not show any evident induction of general toxic or particular immune-toxicologicl effects.

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RATIONALE: Allergen immunotherapy (AIT) is a cost-effective approach and is particularly attractive for a social-security-based healthcare system. Nevertheless, AIT is underdeveloped and hardly available in most Latin American countries. The aim of this work was to review the 20years Cuban experience developing House Dust Mite AIT for asthma METHODS: Standardized allergen extracts were developed for the wellknown species Dermatophagoides pteronyssinus and for the tropical species D.siboney and Blomia tropicalis. The system based on Biological Units using Histamine as standard was used. In addition to IgE activity, Group 1 allergen content was measured. RESULTS: AIT with D. pteronyssinus, as well as, with the relevant tropical species D.siboney and B.tropicalis proved to be highly effective in 9 DBPC clinical trials (3 for each product) in 355 patients. Asthma symptoms decreased down to 56% and 53% after 1-year treatment, by subcutaneous or sublingual routes, respectively. Medication decreased to 58 and 60%. Overall, 76% patients showed clinical improvement, independently of the administration route (OR: 22-40). Products have been progressively introduced country-wide in Cuba, achieving an overall consumption (2008-2016) of roughly 100 000 patient-year treatments. A Phase IV country-wide study performed on 2018 patients has confirmed the efficacy shown in controlled trials. QoL index, medication and asthma symptoms showed highly significant improvements. Sublingual route has shown similar efficacy as compared to injection, with less systemic side-effects and no life-threatening reactions CONCLUSIONS: AIT with standardized HDM allergens has shown to be, not only a clinically advantageous treatment, but also an approach able to be extended into a public healthcare system.