The nave challenge control group tested negative at all time points. and NMC. Our results show that intramuscular administration of WIV can lead to enhanced antibody responses and cross-reactivity in pre-immune subjects, and recall of ASC responses in lymph nodes and NMC. Keywords:influenza, swine, humans, pre-existing immunity, vaccination, heterologous prime-boost, H3N2, antibody cross-reactivity == 1. Introduction == All swine influenza A viruses (SwIAV) of the H3N2 subtype have their hemagglutinin (HA) and neuraminidase (NA) proteins derived from H3N2 viruses that once circulated in humans [1,2]. Repeated transmissions of distinct human-origin viruses to swine have led to an increase in the genetic diversity of SwIAV globally, with strains being confined to their geographical regions of introduction [3]. For instance, H3N2 SwIAV that circulate in European pigs were derived from a human virus that was circulating in the mid-1970s [4]. On the other hand, H3N2 SwIAV that circulate in North American pigs were derived from antigenically distinct human viruses that circulated in the 1990s and in the recent past, in 2011 [1]. This has resulted in the existence of distinct lineages and clusters of H3N2 SwIAV within the same region. These SwIAV have continued to evolve independently from their human counterparts, through either antigenic drift (mutations occurring in genes) or genetic reassortment (mixing of genes in case of simultaneous infections with different strains) with established strains. The rate of evolution of Omeprazole the European SwIAV is much slower as compared with that of the North American SwIAV as well as the human influenza viruses [5,6]. Because variants of human H3N2 influenza viruses keep replacing each other over time, contemporary human H3N2 viruses are genetically and antigenically distinct from those that circulate in swine. Thus, swine serve as reservoirs for the past human viruses, which occasionally jump back to humans [7,8,9,10]. The existence of multiple drift variants of SwIAV poses a great challenge to the effectiveness of vaccines for swine, just as continuous antigenic drift of human influenza viruses does for the human vaccines. In addition, there are no vaccines that can protect humans against zoonotic infections with SwIAV and swine against human influenza viruses. There is, therefore, a strong need for vaccines that can elicit potent and broadly protective immunity against drift variants of influenza viruses of both swine and humans. Heterologous prime-boost vaccination is one strategy that can broaden immune responses to influenza viruses. In studies in humans, poultry, mice, and ferrets, using antigenically distinct strains for primary and booster vaccinations was shown to elicit broad antibody responses against drifted influenza strains within the same HA subtype [11,12,13,14,15,16]. In a previous study, we injected pigs with adjuvanted whole Omeprazole inactivated vaccines (WIV) based on a European H3N2 SwIAV (A/swine/Gent/172/2008, G08) followed 4 weeks later by a North American SwIAV (A/swine/Pennsylvania/A01076777/2010, PA10). This approach stimulated hemagglutination inhibition (HI) antibodies that reacted with 80% of a panel of 15 antigenically distinct H3N2 influenza viruses of both swine and humans. The heterologous prime-boost vaccination strategy was more potent than two administrations of Rabbit polyclonal to RAB18 matched bivalent vaccine or homologous monovalent vaccine. The latter strategy induced antibodies against less than 40% of the tested viruses [17]. While most studies are carried out in influenza-nave animals, humans encounter numerous influenza strains by either infection or vaccination during their lifetime [18,19]. Therefore, most humans have pre-existing immunity to one or several influenza viruses. The effects of pre-existing immunity on responses against vaccination or subsequent infections can Omeprazole either.