title: Safety and immunogenicity in man of a cell culture derived trivalent live attenuated seasonal influenza vaccine: a Phase I dose escalating study in healthy volunteers.
abstract: Live attenuated influenza vaccine (LAIV) offers the promise of inducing a variety of immune responses thereby conferring protection to circulating field strains. LAIVs are based on cold adapted and temperature sensitive phenotypes of master donor viruses (MDVs) containing the surface glycoprotein genes of seasonal influenza strains. Two types of MDV lineages have been described, the Ann Arbor lineages and the A/Leningrad/17 and B/USSR/60 lineages. Here the safety and immunogenicity of a Madin Darby Canine Kidney - cell culture based, intranasal LAIV derived from A/Leningrad/17 and B/USSR, was evaluated in healthy influenza non-naive volunteers 18-50 years of age. In a double-blind, randomized, placebo-controlled design, single escalating doses of 1×10(5), 1×10(6), or 1×10(7) tissue culture infectious dose 50% (TCID50) of vaccine containing each of the three influenza virus re-assortants recommended by the World Health Organization for the 2008-2009 season were administered intranasally. A statistically significant geometric mean increase in hemagglutination inhibition titer was reached for influenza strain A/H3N2 after immunization with all doses of LAIV. For the A/H1N1 and B strains, the GMI in HI titer did not increase for any of the doses. Virus neutralization antibody titers showed a similar response pattern. A dose-response effect could not be demonstrated for any of the strains, neither for the HI antibody nor for the VN antibody responses. No influenza like symptoms, no nasal congestions, no rhinorrhea, or other influenza related upper respiratory tract symptoms were observed. In addition, no difference in the incidence or nature of adverse events was found between vaccine and placebo treated subjects. Overall, the results indicated that the LAIV for nasal administration is immunogenic (i.e. able to provoke an immune response) and safe both from the perspective of the attenuated virus and the MDCK cell line from which it was derived, and it warrants further development.
authors.affiliation: Nobilon International BV, Wim de Körverstraat 35, 5831 AN Boxmeer, The Netherlands. Electronic address: Jacco.Heldens@merck.com.
authors.forename: Jacco
authors.initials: J
authors.lastname: Heldens
authors.affiliation: Merck Sharpe and Dohme Oss BV, Moleneind 110, 5342 CC Oss, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hulskotte
authors.affiliation: Nobilon International BV, Wim de Körverstraat 35, 5831 AN Boxmeer, The Netherlands.
authors.forename: Theo
authors.initials: T
authors.lastname: Voeten
authors.affiliation: Merck Sharpe and Dohme Oss BV, Moleneind 110, 5342 CC Oss, The Netherlands.
authors.forename: Belinda
authors.initials: B
authors.lastname: Breedveld
authors.affiliation: Merck Sharpe and Dohme Oss BV, Moleneind 110, 5342 CC Oss, The Netherlands.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verweij
authors.affiliation: Merck Sharpe and Dohme Oss BV, Moleneind 110, 5342 CC Oss, The Netherlands.
authors.forename: Wilbert
authors.initials: W
authors.lastname: van Duijnhoven
authors.affiliation: Institute of Experimental Medicine, Russian Academy of Medical Sciences, 12 Acad. Pavlov Street, St. Petersburg, 197376, Russia.
authors.forename: Larissa
authors.initials: L
authors.lastname: Rudenko
authors.affiliation: Vaccine & Infectious Diseases Institute (VAXINFECTIO), University of Antwerp, Universiteitsplein 1, B2610 Antwerp, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: van Damme
authors.affiliation: Nobilon International BV, Wim de Körverstraat 35, 5831 AN Boxmeer, The Netherlands.
authors.forename: Han
authors.initials: H
authors.lastname: van den Bosch
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D004285:Dogs; D004311:Double-Blind Method; D005260:Female; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D009981:Influenza B virus; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007251:Influenza, Human / Q000517:prevention & control*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008875:Middle Aged; D014613:Vaccines, Attenuated / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated
keywords: Cell culture; Clinical trial; Healthy volunteers; Influenza; Live attenuated; Phase I; Vaccine