[PubMed] [CrossRef] [Google Scholar] 14. Growing evidence is intimating the possible gains of including the NA antigen in vaccine design, such as expanded strain coverage and paederosidic acid increased overall immunogenicity of the vaccine. After giving a tour of general influenza virology, this review aims to discuss the influenza A virus neuraminidase while focusing on both the historical and present literature on the use of NA as a possible vaccine antigen. family, influenza viruses can be further subdivided into three genera. While viruses from all three genera have been shown to infect humans, only influenza A and B viruses substantially contribute to seasonal epidemics . Furthermore, while influenza B viruses may play a significant role in pediatric influenza cases, surveillance data from the Centers for Disease Control (CDC) has revealed that they tend to cause only a minority ( 20%) of total influenza cases per year . Unlike influenza B and Cwhich are thought to only replicate in human hostsinfluenza A has been shown to infect and replicate in a much broader variety of nonhuman species (including poultry, sea mammals, pigs, horses andmore recentlyNew World bats) . This wide host range has allowed influenza A viruses to acquire much more genetic diversity over evolutionary time compared to counterpart viruses from other genera. Modern taxonomy systems classify existing and emergent influenza A virus subtypes based on the sequence and antigenicity divergence of the virus two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which display the most amino acid sequence diversity out of all influenza virus proteins [3,6]. Since 2009, two additional HA and NA subtypes have been discovered in New World bat species, meaning a total of 18 HA subtypes (H1-18) and 11 NA subtypes (N1-11) have been found in nature thus far (Figure 1) . Only a subset of HAs (H1, H2, and H3) and NAs (N1 and N2) are known to naturally circulate in the human population, although H5, H6, H7, H9, H10, N3, N7, N8, and N9 have been found in human cases mostly associated with poultry outbreaks (Figure 1) [10,11,12,13,14,15,16,17,18]. As viruses of all known subtypes (except the two most recently discovered, H17N10 and H18N11) are maintained in aquatic birds, it is thought paederosidic acid that these species are the natural evolutionary reservoir of the influenza A virus . Open in a separate window Figure 1 Phylogenetic relationships of influenza virus neuraminidase proteins. paederosidic acid (A) Phylogenetic tree of influenza A and B NAs including the recently isolated N10 and N11 subtypes for which no NA activity has been reported. NA subtypes that paederosidic acid circulate in humans are indicated by red stars. Subtypes that occasionally cause human infections are indicated by green stars. (B) Phylogenetic tree of N1 NAs. N1 NAs form three lineages, the avian lineage, which includes the NA of the 2009 2009 pandemic H1N1 virus, the classical swine lineage and the now extinct human lineage. (C) Phylogenetic tree of N2 NAs. N2 forms an avian and a human phylogenetic lineage. The latter one split of from the avian lineage with the 1957 H2N2 pandemic strain and paederosidic acid continued to circulate as Sele H3N2 in 1968 when H2N2 viruses disappeared. (D) Phylogenetic tree of influenza B virus NAs. NAs of prototypic Lee, Yamagata and Victoria strains are indicated. It is of note that the B NAs do not split into the Victoria87 and Yamagata88 lineages like B HA sequences. However, there seems to be a recent split into three distinct lineages with one (HK01-like, 2001 isolate) clustering closest with the.