Influenza B Virus With Modified Hemagglutinin Cleavage Site as a Novel Attenuated Live Vaccine

• Published in: The Journal of infectious diseases 2011-11, Vol.204 (10), p.1483-1490
• Main Authors: Stech, Jürgen, Garn, Holger, Herwig, Astrid, Stech, Olga, Dauber, Bianca, Wolff, Thorsten, Mettenleiter, Thomas C., Klenk, Hans-Dieter
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Viral - blood; Applied microbiology; Biological and medical sciences; Cercopithecine herpesvirus 1; Female; Fundamental and applied biological sciences. Psychology; Hemagglutination, Viral - genetics; Immunization; Infectious diseases; Influenza A virus; Influenza B virus; Influenza B virus - chemistry; Influenza B virus - genetics; Influenza B virus - immunology; Influenza vaccines; Influenza Vaccines - genetics; Influenza Vaccines - immunology; Medical sciences; Mice; Mice, Inbred BALB C; Microbiology; Miscellaneous; Mutation; Orthomyxoviridae; Plaque assay; Transcriptional regulatory elements; Vaccination; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; Virology; Viruses
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jir613

Background. Both pandemic and interpandemic influenza is associated with high morbidity and mortality worldwide. Seasonal epidemics are caused by both influenza A and virus strains that cocirculate with varying predominance and may give rise to severe illness equally. According to World Health Organization recommendations, current annual vaccines are composed of 2 type A and 1 type virus-specific component. Methods. As a novel attenuated live vaccine against influenza virus, we generated a hemagglutinin cleavage site mutant of strain B/Lee/40 by replacing the common monobasic cleavage site recognized by trypsinlike proteases with an elastase-sensitive site, and we investigated the in vitro properties, attenuation, humoral responses, and efficacy in mice. Results. This mutant virus replicated in cell culture equally well as the wild type but in a strictly elastasedependent manner. In contrast to the mouse-pathogenic parental virus, the cleavage site mutant was fully attenuated in mice and not detectable in their lungs. After 1 intranasal immunization, the animals survived lethal challenge with wild-type virus without weight loss or any other signs of disease. Furthermore, no challenge virus could be reisolated from the lungs of vaccinated mice. Conclusions. These findings demonstrate that proteolytic activation mutants can serve as live vaccine against influenza virus.