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Title:   Author  item
                                            RAJÃO, DANIELA - Non ARS Employeeitem
                                            CHEN, HONGJUN - University Of Marylanditem
                                            PEREZ, DANIEL - University Of Marylanditem
                                            SANDBULTE, MATTHEW - Iowa State Universityitem
                                            GAUGER, PHILLIP - Iowa State Universityitem
                                            Loving, Crystalitem
                                            SHANKS, G. DENNIS - Collaboratoritem
                                            Baker, Amy
  Submitted to: Journal of General Virology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 3/29/2016
                                    Publication  Date: 3/31/2016
                                    Citation: Rajão, D.S., Chen, H., Perez, D.R., Sandbulte, M.R., Gauger, P.C., Loving, C.L., Shanks, G., Vincent, A.L. 2016. Vaccine-associated enhanced respiratory disease is influenced by hemagglutinin and neuraminidase in whole inactivated influenza virus vaccines. Journal of General Virology. 97(7):1489-1499.Interpretive Summary: Subtypes of influenza A virus (IAV) are composed of different types of hemagglutinin (HA) and neuraminidase (NA), with H1N1, H1N2 and H3N2 subtypes being endemic in swine worldwide. Many variants of IAV co-circulate in pigs in the United States, complicating the control of influenza through the use of commercial vaccines. Whole inactivated virus (WIV) vaccines are widely used by the swine industry, but only provide partial protection against distinct IAV and have been shown to induce vaccine-associated enhanced respiratory disease (VAERD) when the challenge strain is mismatched to the vaccine strains. Our previous VAERD studies focused on the surface protein, HA, but here we expanded our studies to include NA. Mismatched HA between vaccine and challenge virus was necessary to induce VAERD, but vaccines with matched NA blocked the VAERD phenomenon produced by the HA mismatch. In contrast, divergence between NA lineages resulted in a loss of NA-inhibiting (NI) antibody cross-reactivity and also resulted in VAERD with the mismatched HA. Thus, the combination of HA and NA in the vaccine virus strains played substantial roles in vaccine protection versus vaccine-enhanced disease. These results demonstrate the importance of the NA in vaccine composition.
                                Technical Abstract: Multiple subtypes and many antigenic variants of influenza A virus (IAV) co-circulate in swine in the USA, complicating effective use of commercial vaccines to control disease and transmission. Whole inactivated virus (WIV) vaccines may provide partial protection against IAV with substantial antigenic drift, but have been shown to induce vaccine-associated enhanced respiratory disease (VAERD) when challenged with an antigenic variant of the same hemagglutinin (HA) subtype. This study investigated the role the immune response against HA, neuraminidase (NA), and nucleoprotein (NP) may play in VAERD by reverse engineering vaccine and challenge viruses on a common backbone and using them in a series of vaccination/challenge trials. Mismatched HA between vaccine and challenge virus was necessary to induce VAERD. However, vaccines containing a matched NA abrogated the VAERD phenomenon induced by the HA mismatch and was correlated with NA-inhibiting (NI) antibodies. Divergence between the two circulating swine N2 lineages (92% identity) resulted in a loss of NI cross-reactivity and also resulted in VAERD with the mismatched HA. The NP lineage selected for use in the WIV vaccine strains did not affect protection or pathology. Thus the combination of HA and NA in the vaccine virus strains played substantial roles in vaccine protection versus immunopathology, suggesting that vaccines that target the HA protein alone could be more prone to VAERD due to the absence of cross-protective NI antibodies.


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