title: Development and pre-clinical evaluation of two LAIV strains against potentially pandemic H2N2 influenza virus.
abstract: H2N2 Influenza A caused the Asian flu pandemic in 1957, circulated for more than 10 years and disappeared from the human population after 1968. Given that people born after 1968 are naïve to H2N2, that the virus still circulates in wild birds and that this influenza subtype has a proven pandemic track record, H2N2 is regarded as a potential pandemic threat. To prepare for an H2N2 pandemic, here we developed and tested in mice and ferrets two live attenuated influenza vaccines based on the haemagglutinins of the two different H2N2 lineages that circulated at the end of the cycle, using the well characterized A/Leningrad/134/17/57 (H2N2) master donor virus as the backbone. The vaccine strains containing the HA and NA of A/California/1/66 (clade 1) or A/Tokyo/3/67 (clade 2) showed a temperature sensitive and cold adapted phenotype and a reduced reproduction that was limited to the respiratory tract of mice, suggesting that the vaccines may be safe for use in humans. Both vaccine strains induced haemagglutination inhibition titers in mice. Vaccination abolished virus replication in the nose and lung and protected mice from weight loss after homologous and heterologous challenge with the respective donor wild type strains. In ferrets, the live attenuated vaccines induced high virus neutralizing, haemagglutination and neuraminidase inhibition titers, however; the vaccine based on the A/California/1/66 wt virus induced higher homologous and better cross-reactive antibody responses than the A/Tokyo/3/67 based vaccine. In line with this observation, was the higher virus reduction observed in the throat and nose of ferrets vaccinated with this vaccine after challenge with either of the wild type donor viruses. Moreover, both vaccines clearly reduced the infection-induced rhinitis observed in placebo-vaccinated ferrets. The results favor the vaccine based on the A/California/1/66 isolate, which will be evaluated in a clinical study.
authors: Institute for Experimental Medicine, Saint Petersburg, Russia.
authors: Irina
authors: I
authors: Isakova-Sivak
authors: Centre for Infectious Disease Control, RIVM, Bilthoven, the Netherlands.
authors: Jørgen
authors: J
authors: de Jonge
authors: Institute for Experimental Medicine, Saint Petersburg, Russia.
authors: Tatiana
authors: T
authors: Smolonogina
authors: Institute for Experimental Medicine, Saint Petersburg, Russia.
authors: Andrey
authors: A
authors: Rekstin
authors: Animal Research Center, InTraVacc, Bilthoven, the Netherlands.
authors: Geert
authors: G
authors: van Amerongen
authors: Centre for Infectious Disease Control, RIVM, Bilthoven, the Netherlands.
authors: Harry
authors: H
authors: van Dijken
authors: Centre for Infectious Disease Control, RIVM, Bilthoven, the Netherlands.
authors: Justin
authors: J
authors: Mouthaan
authors: Microscope Consultancy, Weesp, the Netherlands.
authors: Paul
authors: P
authors: Roholl
authors: Institute for Experimental Medicine, Saint Petersburg, Russia.
authors: Victoria
authors: V
authors: Kuznetsova
authors: Institute for Experimental Medicine, Saint Petersburg, Russia.
authors: Elena
authors: E
authors: Doroshenko
authors: PATH Vaccine Development Global Program, Seattle, Washington, United States of America.
authors: Vadim
authors: V
authors: Tsvetnitsky
authors: Institute for Experimental Medicine, Saint Petersburg, Russia.
authors: Larisa
authors: L
authors: Rudenko
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005289:Ferrets; D015870:Gene Expression; D006389:Hemagglutinins, Viral / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D053121:Influenza A Virus, H2N2 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000821:virology; D051379:Mice; D008808:Mice, Inbred CBA; D009439:Neuraminidase / Q000235:genetics / Q000276:immunology; D009666:Nose / Q000187:drug effects / Q000276:immunology / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D058873:Pandemics / Q000517:prevention & control*; D016865:Reassortant Viruses / Q000235:genetics / Q000276:immunology*; D014613:Vaccines, Attenuated; D014779:Virus Replication
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D006389:Hemagglutinins, Viral; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D009439:Neuraminidase