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.
Highlights
IntroductionPandemics caused by influenza variants to which the population was naıve occurred four times during the last century
Seasonal epidemics of influenza virus annually cause significant disease burden [1]
3.1 Generation of H2N2 live attenuated influenza vaccine (LAIV) reassortants For our study we selected two wild-type viruses A/Tokyo/3/67 (H2N2) (A/Tok/3/67) and A/California/1/66 (H2N2) (A/Cal/ 1/66), which belong to two divergent lineages that circulated at the end of H2N2 wave [13]
Summary
Pandemics caused by influenza variants to which the population was naıve occurred four times during the last century. These were characterized by very rapid spread, affected entire continents or the whole world with morbidity rates considerably above normal and excess mortality in some population groups. This highlights the seriousness of the threat to mankind that lies in possible future pandemics. The virus subtypes H1, H2, and H3 which are known to have caused previous pandemics have the highest level, and H5, H6, H7, and H9 have high level of priority [2]
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