H1N1 INFLUENZA A VIRUS IN SWINE SUPPLEMENTAL RESEARCH PROGRAM
Location: Virus and Prion Research Unit
Title: Overview of swine influenza virus vaccine research and technology: What's on the horizon and what do we need to move forward?
Submitted to: American Association of Swine Veterinarians Annual Meeting
Publication Type: Proceedings
Publication Acceptance Date: November 29, 2012
Publication Date: March 13, 2013
Citation: Kehrli, Jr., M.E., Vincent, A.L., Gauger, P.C., Kitikoon, P., Anderson, T.K., Loving, C.L., Lager, K.M. 2013. Overview of swine influenza virus vaccine research and technology: What's on the horizon and what do we need to move forward? In: Proceedings of 44th Annual Meeting of the American Association of Swine Veterinarians, San Diego, CA. p. 517-519.
Swine influenza represents a problem for the health of pigs and the economic health of the swine industry due to real and perceived public health risks. This is largely driven by the diversity of influenza A viruses (IAV) in swine herds. Antigenic drift (mutations) and shifts (reassortments) by influenza viruses are continually occurring. The RNA polymerase error rate among IAV is ~2 X 10**-3 nucleotide substitutions/site/year(1) and whenever a single cell is infected by 2 different influenza viruses, reassortment events between the viruses can occur and result in as many as 256 different gene combinations. These 2 types of genetic change provide the basis of the marked genetic and antigenic diversity in contemporary IAV in North American swine. In addition, interspecies transmission is an important contributor to the genetic diversity of IAV found in swine. For example, at least 23 separate human-to-swine transmission events of human seasonal H1 and H3 influenza viruses have been identified globally since 1990.(2)
The global ecology of influenza A viruses (IAV) in swine can be separated by geographic regions, with North American lineages genetically distinct from European swine lineages. In North America, the classical swine H1N1 virus was dominant until the seasonal human H3N2 virus was introduced into pigs in 1998(3) and followed by at least two additional, separate introductions of human H1 viruses.(4) At present, seven major antigenically distinct hemagglutinin (HA) lineages, H1alpha, H1beta, H1gamma, H1delta1, H1delta2, H1N1pdm09 and H3 cluster IV (c4) co-circulate in North American swine populations.(5) Until 2009, all dominant HA lineages except for the H1N1pdm09 virus contained the 'triple reassorted internal gene' (TRIG) constellation of swine (M, NP and NS genes), avian (PB2 and PA genes), and human (PB1) lineages identified in swine in 1998. The internal gene constellation in H1N1pdm09 is distinct from the H3N2-TRIG as the M gene is of Eurasian swine lineage and the other 5 genes can be differentiated in a phylogenetic analysis.(6) Within two years after the emergence of H1N1pdm09 in humans, at least 49 influenza spillover events from humans-to-swine were detected globally.(2) The introduction of H1N1pdm09 into pigs subsequently led to multiple reassortment events between H1N1pdm09 and the endemically circulating IAV of swine, greatly increasing the genetic diversity of IAV in swine.(7)
Public health concerns impact swine influenza vaccination needs
Nothing has highlighted the economic impact of IAV on swine production more than the emergence of the H1N1pdm09. The H3N2-TRIG/H1N1pdm09 (rH3N2p) reassortant viruses are of particular public health concern in the United States; between August 2011 and November 2012, there have been 319 human infections (http://www.cdc.gov/flu/swineflu/h3n2v-case-count.htm) by a variant comprised of 7 genes from swine H3N2 and the M gene of H1N1pdm09 (H3N2v).(8,9) The number of H3N2v human cases highlights the need for IAV whole genome characterization to further understand the evolution of reassortant H3N2/H1N1pdm09 (rH3N2p) viruses in swine and humans, and may indicate a need for vaccine or diagnostic assay updates for both populations. In veterinary medicine, we have a higher bar to clear than to simply protect against clinical disease in pigs. Indeed, the human-to-swine and swine-to-human transmission pathways suggest that a vaccine priority should be protection and prevention against transmission of viruses from pigs to other pigs and from pigs to people. This is a much more difficult goal than what is required for human vaccines and current inactivated vaccines are not adequately addressing the public nor swine health issues the industry faces.
Currently available vaccines
Currently in the United States among 4 vaccine manufacturers, there are 30 licensed swine influenza products. All of these vaccines are considered killed virus products; many of which are combined with bacterins in a single product. For the past several years in the United States, autogenous vaccines represent at least half of the swine influenza virus (SIV) vaccine doses produced. Although it appears that producers have many options for preventing IAV, none have provided adequate protection.
What is on the horizon?
Research in swine on live-attenuated IAV vaccines (LAIV) has repeatedly demonstrated their general safety and superior efficacy to inactivated vaccines.(10-20) DNA-based(21) and vectored vaccines have also demonstrated efficacy against IAV and have advantages over inactivated vaccines.(22-25) Current research is investigating how effective these vaccines are in protecting against shedding of circulating IAV when vaccinated pigs are exposed to homologous or heterologous IAV. Experimental data have demonstrated that attenuated vaccines are superior in their ability to protect against transmission of challenge viruses to naïve contact pigs. Further, these data have highlighted the importance of including contemporary strains in vaccine cocktails to increase antigenic coverage of circulating viral diversity.
What is the target for efficient vaccines for swine?
We propose that an integrated multi-agency approach is needed to improve IAV vaccine strain selection for use in swine. Ideally this would include representatives from ARS, APHIS, NAHLN labs, and industry. To make this work, the USDA SIV Surveillance System must continue to monitor contemporary viruses identified in cases of respiratory disease outbreak investigations through veterinary/producer participation and submissions to NAHLN labs. These data may be used by bioinformaticists to describe contemporaneous spatio-temporal trends in subtype and genetic diversity, and long-term patterns of transmission and evolution. Representative viruses from predominant subtypes or genotypes should be evaluated at an antigenic level for serologic cross-reactivity with anti-sera from vaccinated swine. New swine antisera should be generated with IAV that have drifted antigenically or with newly added vaccine strains. In vivo swine studies should be conducted when IAV with substantial changes have been identified or when vaccine strains have been substantially changed.
We suggest one or more IAV backbones would be approved by the Center for Veterinary Biologics (CVB) for ease of quickly generating viruses with new and relevant HA and neuraminidases (NA) for vaccine purposes. Initially, these virus backbones should be demonstrated to provide attenuation in the case of LAIV as well as exhibiting high yield growth properties as a vaccine seed for IAV vaccines for use in swine. The advantages to this are:
• Not all field strains provide sufficient antigenic mass of HA and this would facilitate the ease of testing several representative strains to select the optimal isolate.
• Not all field strains grow well in cell-culture and this would facilitate the ease of testing several representative strains to select the optimal isolate.
• Reduces the risk of introducing extraneous agents from field isolates.
By way of traditional reassortment or reverse genetics, licensed manufacturers generate reassortant viruses with relevant HA and NA found to circulate in pigs or that pose a significant risk to pigs (like the 2009 pandemic virus first found in humans) in order to meet the industry's needs. A company should be required to notify CVB of the HA and/or NA sequences being incorporated onto the approved backbone, adhere to previously approved Good Manufacturing Process practices, and market vaccine updates without delay. Minimal safety and efficacy data should be required if the previously approved seed strain backbone and vaccine formulation is used, but should minimally demonstrate strong cross-protection against homologous and heterologous contemporary strains. Companies may select HA and NA sequences from the USDA SIV surveillance system or from their own internal surveillanc
Last Modified: 06/19/2013