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  • Clinical assessment of safety and immunogenicity of mucosal influenza vaccines for intranasal administration in human by means of an ad hoc proof of concept clinical trial. Comparison with conventiona

Clinical assessment of safety and immunogenicity of mucosal influenza vaccines for intranasal administration in human by means of an ad hoc proof of concept clinical trial. Comparison with conventiona

The phase I clinical trial was performed in Leicester, involving recruitment, immunization and monitoring of 84 volunteers. A particular effort was placed on careful monitoring for the possible occurrence of side effects.

No patient was lost to follow-up, and no relevant side effects were noticed after intranasal or intramuscular immunisation.

Furthermore, samples of blood, nasal secretions and crevicular fluid were collected and delivered to partners K. Mills, J. Holmgren and M. Zambon for analysis. A special arrangement had to be set to deliver samples by air courier to K. Mills, performing studies of cell-mediated immunity, which required same-day delivery.Ad hoc individual case report forms (CRFs) were filled by the investigators and sent to Chiron Vaccines data management center in Amsterdam, The Netherlands, in order to be entered into the clinical database. Data were subsequently fully analysed and reported in a clinical study report.

The clinical trial performed in this period provided a number of relevant information: 1.A nasal trivalent influenza vaccine containing the non-toxic LT mutant LTK63 is very well tolerated and is able to induce a systemic immune response against influenza B and, to a lesser extent, against H3N2 antigens.2.A dose-dependent mucosal immune response against all the flu antigens included in the vaccine was observed in the nose after nasal immunization.3.No systemic immune response could be detected against the pandemic antigen H5N3 after nasal immunization. Furthermore, the systemic immune response against the other antigens was observed only at the highest dose of LT mutant. Therefore, a higher dose of adjuvant, a mutant with stronger adjuvant activity (such as LTR72) or/and a different schedule of administration could be necessary for optimal immunization against these antigens. In particular, studies of cell-mediated immunity suggested that a longer interval could be needed between the first and the second immunization, to allow the development of immunologic memory particularly against the pandemic strain.

Two additional findings of great practical interest were found in the study:4.

The systemic immune response against H5N3 observed in the control group immunized by the intramuscular route, was similar to the one previously observed using a monovalent vaccine. Therefore the pandemic antigen can be formulated in a trivalent vaccine without loss of activity.5.A marked increase in nasal specific IgG against the three flu antigens was observed after parenteral immunization. Thus, local immunoglobulins might participate in the protective effect of the intramuscular vaccine, in addition to the systemic immune response.

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