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Title: Natural immunity to influenza virus in humans following 2009 pandemic H1N1 influenza
Author: Mahallawi, Waleed
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2013
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Influenza is a highly contagious and acute respiratory infection caused by influenza virus in the mucosa of the respiratory tract. Both seasonal and pandemic influenza continue to cause substantial morbidity and mortality in humans. The 2009 pandemic H1N1 (pH1N1) influenza and the potential of a highly pathogenic avian H5N1 (aH5N1) pandemic highlighted the need for effective preventative strategies. Understanding the development of natural immunity following the pH1N1 pandemic may provide important information on host protective immunity in humans, which could inform future more effective vaccination strategies against influenza. In this thesis, naturally developed mucosal immunity to 2009 pH1N1 virus was studied in children and adults using cells derived from human nasal-associated lymphoid tissue (NALT). Firstly, the frequency of HA-specific memory B cells in human NALT to pH1N1 virus and their ability to produce cross-reactive antibodies were studied. Patients who had serological evidence of previous exposure to pH1N1 virus developed large numbers of IgG memory B cells in NALT that produce crossreactive neutralizing antibodies against a number of influenza subtypes upon pH1N1 virus antigen stimulation. The presence of such memory B cells in human NALT appears to have primed the host for cross-reactive mucosal memory response against other H1N1 and the highly pathogenic aH5N1 virus strains. These findings may have important implications in future vaccination strategies against influenza. Secondly, serum specific anti-pH1N1 HA IgG antibodies were analysed using ELISA. HA-specific antibody levels to pH1N1 in adults were significantly higher than that of children. The results may suggest that adults had been exposed to more cross-reactive influenza viruses than children, and developed more cross-reactive memory responses against some influenza viruses than in children. Significantly higher HA-specific IgG antibody titres to pH1N1 HA (measured using ELISA) were found in subjects who had HAI titres≥40 than in those with HAI antibody titre<40. This suggests that following the 2009 pH1N1 pandemics, large numbers of people developed anti-pH1N1 HA antibodies to both the circular head and the stalk regions of HA which may have broader protective immunity. Thirdly, HA-specific memory CD4+ T cell response to pH1N1 virus was shown in tonsillar cells from children and adults. This suggests that following the 2009 pandemic H1N1 influenza, humans developed memory T cell response to the pH1N1 HA protein antigen at the mucosal level in the nasopharynx. There appeared to be an age-associated increase in this memory response. Finally, mucosal antibody responses in NALT to HAs of a number of influenza A viruses were investigated following in vitro stimulation of adenotonsillar cells with LAIV vaccine which contains a 2009 pandemic H1N1 virus, a seasonal H3N2 and a B influenza strain. Significant antibody responses of all 3 isotypes (IgG, IgA and IgM) to the HA of pandemic H1N1 virus were observed in tonsillar cells following LAIV stimulation. It suggests that the in vitro model of human NALT using adenotonsillar cell culture could be used to study the LAIV-induced immune responses which may predict the immunogenicity and efficacy of candidate LAIV vaccines in humans.
Supervisor: Zhang, Qibo; McNamara, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available