The Matrix Gene Segment Destabilizes the Acid and Thermal Stability of the Hemagglutinin of Pandemic Live Attenuated Influenza Virus Vaccines
Open Access
- 1 November 2014
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 88 (21), 12374-12384
- https://doi.org/10.1128/jvi.01107-14
Abstract
The threat of future influenza pandemics and their potential for rapid spread, morbidity, and mortality has led to the development of pandemic vaccines. We generated seven reassortant pandemic live attenuated influenza vaccines (pLAIVs) with the hemagglutinin (HA) and neuraminidase (NA) genes derived from animal influenza viruses on the backbone of the six internal protein gene segments of the temperature sensitive, cold-adapted ( ca ) A/Ann Arbor/60 (H2N2) virus (AA/60 ca ) of the licensed seasonal LAIV. The pLAIV viruses were moderately to highly restricted in replication in seronegative adults; we sought to determine the biological basis for this restriction. Avian influenza viruses generally replicate at higher temperatures than human influenza viruses and, although they shared the same backbone, the pLAIV viruses had a lower shutoff temperature than seasonal LAIV viruses, suggesting that the HA and NA influence the degree of temperature sensitivity. The pH of HA activation of highly pathogenic avian influenza viruses was greater than human and low-pathogenicity avian influenza viruses, as reported by others. However, pLAIV viruses had a consistently higher pH of HA activation and reduced HA thermostability compared to the corresponding wild-type parental viruses. From studies with single-gene reassortant viruses bearing one gene segment from the AA/60 ca virus in recombinant H5N1 or pH1N1 viruses, we found that the lower HA thermal stability and increased pH of HA activation were associated with the AA/60 M gene. Together, the impaired HA acid and thermal stability and temperature sensitivity likely contributed to the restricted replication of the pLAIV viruses we observed in seronegative adults. IMPORTANCE There is increasing evidence that the HA stability of influenza viruses depends on the virus strain and host species and that HA stability can influence replication, virulence, and transmission of influenza A viruses in different species. We investigated the HA stability of pandemic live attenuated influenza vaccine (pLAIV) viruses and observed that the pLAIV viruses consistently had a less stable HA than the corresponding wild-type influenza viruses. The reduced HA stability and temperature sensitivity of the pLAIV viruses may account for their restricted replication in clinical trials.Keywords
This publication has 77 references indexed in Scilit:
- Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferretsNature, 2012
- An open label Phase I trial of a live attenuated H6N1 influenza virus vaccine in healthy adultsVaccine, 2011
- The influence of the multi-basic cleavage site of the H5 hemagglutinin on the attenuation, immunogenicity and efficacy of a live attenuated influenza A H5N1 cold-adapted vaccine virusVirology, 2009
- A live attenuated H7N3 influenza virus vaccine is well tolerated and immunogenic in a Phase I trial in healthy adultsVaccine, 2009
- A Live Attenuated H9N2 Influenza Vaccine Is Well Tolerated and Immunogenic in Healthy AdultsThe Journal of Infectious Diseases, 2009
- A live attenuated cold-adapted influenza A H7N3 virus vaccine provides protection against homologous and heterologous H7 viruses in mice and ferretsVirology, 2008
- Analysis of residues near the fusion peptide in the influenza hemagglutinin structure for roles in triggering membrane fusionVirology, 2007
- Mechanisms of Acid and Base Secretion by the Airway EpitheliumThe Journal of Membrane Biology, 2006
- Studies using double mutants of the conformational transitions in influenza hemagglutinin required for its membrane fusion activityProceedings of the National Academy of Sciences of the United States of America, 1996
- Fusion mutants of the influenza virus hemagglutinin glycoproteinCell, 1985