Design and recruitment for the GAP trial, investigating the preventive effect on asthma development of an SQ-standardized grass allergy immunotherapy tablet in children with grass pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: Allergic rhinoconjunctivitis is a risk factor for asthma development. Treating the underlying allergy may represent an attractive method of asthma prevention. No regulatory guidance exists in this area, and, to our knowledge, no clinical investigations meeting modern regulatory standards have been published. OBJECTIVE: The objective of this publication is to describe the rationale behind the design of and report on the recruitment for the ongoing pediatric Grazax Asthma Prevention (GAP) trial. METHODS: The trial was designed for assessment of the preventive effect of an SQ-standardized grass allergy immunotherapy tablet (AIT) on asthma development, both during treatment and after the end of treatment. (The standardized quality [SQ] procedure is a standardization procedure comprising 3 components: total potency, major allergen content, and assessment of extract complexity.) The trial design was discussed with several European Competent Authorities. RESULTS: The GAP trial is a multinational, parallel-group, double-blind, placebo-controlled randomized trial. Main eligibility criteria were age of 5 to 12 years, grass pollen-induced allergic rhinoconjunctivitis, no asthma, and no overlapping symptomatic allergies. The children have been randomized 1:1 to receive the grass AIT or placebo once daily for 3 years, followed by a blinded observational period of 2 years. Asthma is assessed by the investigators according to specific diagnostic criteria, used at screening visits before randomization to exclude children with existing asthma, and evaluated at least half-yearly during the trial. Seven months of screening resulted in 812 randomized children at 101 centers in 11 countries. CONCLUSIONS: To our knowledge, the GAP trial represents the first double-blind, placebo-controlled randomized trial to assess the preventive effect of allergen-specific immunotherapy on asthma development. A total of 812 children were successfully recruited into the trial. EudraCT number: 2009-011235-12.

A non-living nasal influenza vaccine can induce major humoral and cellular immune responses in humans without the need for adjuvants.

Twenty-eight healthy adult volunteers were immunized intranasally with an inactivated whole-virus influenza vaccine based on the strain A/New Caledonia/20/99 (H1N1), either in saline or mixed with formaldehyde-inactivated Bordetella pertussis as a mucosal adjuvant, or in a thixotropic vehicle with mucoadhesive properties. After four doses, all groups of vaccinees developed significant IgG- and IgA-antibody responses, measured by ELISA, in respectively serum and nasal secretions. None of the volunteers had demonstrable hemagglutination inhibition (HAI) antibodies in serum before being immunized, whereas more than 80% of them reached HAI titers>or=40, considered protective, after immunizations. In addition, cellular immune responses, measured as significant increases in CD4+ T-cell proliferation and granzyme B-producing cytotoxic T-cells, were detected against the vaccine strain as well as against heterologous virus strains (H3N2). However, no additive effect on these responses could be demonstrated with use of B. pertussis or the thixotropic substance in the present vaccines. It appeared, actually, that the mucoadhesive vehicle containing the thixotropic substance was less efficient than were the two other formulations. An influenza vaccine made as a simple particulate formulation of inactivated virus, and given repeatedly onto the nasal mucosa, may thus be an attractive alternative to currently available vaccines.

Bordetella pertussis can act as adjuvant as well as inhibitor of immune responses to non-replicating nasal vaccines.

In mice immunised intranasally with an inactivated whole-virus influenza (INV) vaccine, or ovalbumin (OVA), formalin-inactivated Bordetella pertussis (Bp) augmented antibody responses to the same degree as did cholera toxin (CT) when simply being mixed with INV or OVA. In order to study possible non-carrier effects of mucosal adjuvants, mice were given Bp or CT intranasally 1 day before or 1 day after the INV vaccines. At high antigen doses, both Bp and CT had an adjuvant effect on antibodies in serum also when given 1 day after the vaccine. However, Bp and CT inhibited such antibody responses in serum and saliva when given 1 day ahead of the vaccine. This inhibitory effect was most marked at low antigen doses, i.e. when the adjuvant effect was less obvious. In that event, Bp also inhibited responses in serum and saliva when given 1 day after the INV vaccine. The inhibition of these responses may thus depend on Bp and CT themselves being strongly immunogenic, and competing with INV for the functional capacity of the mucosal immune system.