Influenza A virus vaccines for swine

Abstract

Economic losses due to influenza A virus (IAV) infections are substantial and a global problem, ranking among the top three major health challenges in the swine industry. Currently, H1 and H3 subtypes circulate in pigs globally associated with different combinations of N1 and N2 subtypes; however, the origin, gene constellation, and antigenic makeup of IAV vary greatly on different continents. Vaccination is one means of mitigating the effects of IAV disease, and vaccines are most effective if the strains included closely match the currently circulating strains in pigs. Genetic analyses provide panoramic views of the virus landscape at the sequence level and, thus, can aid in the selection of well-matched swine IAV vaccine strains, but is not sufficient alone. Additionally, a major challenge in selecting appropriate swine IAV vaccine strains is the co-circulation of multiple lineages of viruses in the same region, requiring multivalent or broadly cross-reacting antigens. Due to this complex IAV ecology in swine, new vaccination strategies and vaccine platforms are needed. The hemagglutinin (HA) viral protein is the major target of neutralizing antibodies, which are widely considered to be correlated with protection. Virus variants that are not recognized by previously elicited antibodies can render traditional vaccines that primarily elicit humoral responses ineffective, and therefore result in the need for vaccine strain reformulation and re-vaccination. In the future, new vaccine platforms may be on the market that will provide alternative options to those currently available. Nonetheless, a collaborative approach is needed to improve IAV vaccine strain selection for use in swine.

Keywords: H1N1; H1N2; H3N2; Influenza A virus; Swine; Vaccines.

Fig. 1.

Phylogeny of H1 and H3 influenza A virus hemagglutinin gene sequences from 2000 to present. (A) The best-known tree generated using maximum likelihood methods of 4629 swine and representative human H1 gene sequences is shown: major genetic lineages are labeled, and branch color represents continent of collection. The clade labeled H1N1pdm09 includes HA collected from 34 countries and all continents other than Antarctica. (B) The best-known tree generated using maximum likelihood methods of 1782 swine and representative human H3 gene sequences is shown: branch color represents continent of collection. The geographic groups (data available upon request) include: North America with data from Canada, Mexico, and USA; Central and South America with data from Argentina, Brazil, Chile, Colombia, Costa Rica, Guatemala, and Peru; Europe with data from 12 countries; South Asia with data from Sri Lanka and India; East Asia with data from China, Hong Kong, Japan, South Korea, and Taiwan; and Southeast Asia with data from Singapore, Thailand, and Viet Nam. The trees were midpoint rooted for clarity, all branch lengths are drawn to scale, and the scale bar indicates the number of nucleotide substitutions per site. These analyses used the computational resources of the USDA-ARS computational cluster Ceres on ARS SciNet (www.scinet.usda.ars.gov).

Fig. 2.

Structure of surveillance for influenza A virus (IAV) in swine. The foundation of a surveillance system is diagnostic screening for presence of IAV. At each level, the number of samples to test are reduced by screening and analyses to identify IAV of interest, but the level of complexity for each subsequent stage increases, allowing for fewer specialized entities to contribute. The ultimate goals of an integrated and collaborative IAV surveillance network are to monitor and report genetic and antigenic evolution to inform animal and public health sectors, update diagnostics and vaccines as needed, identify relevant strains for further research, and to develop and implement improved intervention strategies.

Fig. 3.

Evolutionary relationships of H1 (A, B) and H3 (C, D) influenza viruses circulating in swine and humans inferred by Bayesian Multi-dimensional scaling (BMDS). Each colored ball represents a single virus. Viruses are colored by lineage (A,C) and by geography (B,D). Lines connecting each virus represent inferred phylogenetic relationships. Distances for antigenic dimensions are measured in antigenic units (AU) and each unit is equivalent to a two-fold dilution in HI assay data. Viruses close to one another are more antigenically similar than viruses further apart. Reprinted from Lewis et al., 2016; doi:10.7554/eLife.12217.003.

Fig. 4.

Vaccine platform and route of administration influence the resulting immune response. Whole inactivated vaccines (WIV) are administered parenterally through intramuscular routes whereas live attenuated influenza vaccines (LAIV) are typically delivered mucosally through intranasal routes. Vectored or RNA vaccines may be delivered through either route. The route of administration as well as the manner in which vaccine antigens are presented to the immune system influences the resulting host immune response.