Live Attenuated Influenza Vaccine (LAIV) Immunization in Children and Adults: Lesson for Development of Universal Influenza Vaccine

Abstract

According to the WHO (World Health Organization), one billion peoples are infected annually of whom three to five millions become severely ill and 250-500 000 deaths worldwide (He, Wang et al. 2013) although the latest research reported 291-645 000 deaths each year (4.0-8.8 per one hundred thousand individuals). Occasional pandemics cause even higher rates of mortality. Controlling influenza infection is a frontline problem for human health. Vaccination is considered the best strategy for reducing influenza infection. However, antigenic drift of influenza requires updating of the vaccine each year to match the circulating virus strains to provide optimal vaccine efficacy. Currently, two different types of vaccines are in clinical use; trivalent inactivated vaccines (TIV) and trivalent live attenuated influenza vaccines (LAIV). Quadrivalent LAIV is also approved and used in some countries. The majority of currently approved seasonal influenza vaccines are TIV, delivered intramuscularly or deep subcutaneously, which can further be subdivided as splitvirion vaccines and subunit vaccine based on their formulations (Toback, Levin et al. 2012). On the other hand, only one LAIV is licensed in the USA and Europe for specific at risk populations. The vaccine compromises live attenuated influenza viruses produced by reverse genetics that can replicate efficiently (Coelingh, Luke et al. 2014). Moreover, live attenuated, cold-adaptive, trivalent influenza virus vaccine is administered intranasally representing a convenient, safe and effective approach for the prevention of influenza in children (Belshe, Mendelman et al. 1998). However, strain-matched vaccines often lag behind the antigenic changes in the virus and in the event of a pandemic, there is a time lag of at least six months before the vaccine is available (Epstein and Price 2010). Thus, the concept of ‘universal influenza vaccine’ is under discussion to reduce all influenza A virus infections by providing broad cross-reactive (heterosubtypic) immunity. Several studies have shown that LAIV can boost virus-specific cytotoxic T lymphocytes, as well as mucosal and serum antibodies and induce broad cross-protection against heterologous human influenza A viruses (He, Wang et al. 2013). Although the integrated approach provides evidence of cross-protective immunity, the underlying mechanism is poorly understood. This research project therefore mainly addressed some of the fundamental research questions of how LAIV provides protective immunity. We have been shown a significant elevated neutralizing antibody response after LAIV in children measured by haemagglutinin inhibition (HI) assay. Further we dissected haemagglutinin (HA) to head and stalk antibody responses, we observed in children that LAIV significantly elicited H3 head specific antibodies. H1 stalk specific antibodies were also increased but not significantly. In contrast in adults, LAIV did not boost antibody responses (Paper I). We found that H1N1pdm09 virus specific humoral immunity was not boosted in general, although NAI responses were elevated in children. CD4 T-cell responses in blood were also induced against H1N1 vaccine strain. Influenza specific IFN-γ responses increased in children as well (Paper II). The influenza B strain specific IFN-γ responses increased both locally (TMNC) and systemically (PBMC). LAIV resulted in a significant increase in CD8+ T-cell responses post-vaccination in the tonsils suggesting LAIV is able to induce cross-reactive local CD8+ T-cells in the upper respiratory tract (Paper III). In contrast to the observation in USA, our overall results illustrated in this thesis correspond to the response found in other European countries, like UK and Finland. Our finding suggest that the H1N1 vaccine strain in LAIV may have protected children through NAI and T cellular responses, suggesting support for continued use of live attenuated influenza vaccine for children. The multifaceted immune response following LAIV immunization in children suggests LAIV could be used as future universal vaccine for children.