Characterization of virus strain- and pig age-dependence of porcine epidemic diarrhea virus: Implications for vaccine development
Porcine epidemic diarrhea virus (PEDV) is the causative agent of porcine epidemic diarrhea, an enteric disease affecting pigs of all ages that impacts the global swine industry. Although PEDV was first identified in Europe in 1970s and spread to some Asian countries thereafter, PEDV did not emerge in the United States until 2013. Since then, two main strains of PEDV have been circulating in U.S. swine herds: non-S INDEL and S INDEL PEDVs. While two commercially available vaccines (one killed PEDV vaccine and one RNA particle PEDV vaccine) exist in the U.S., their efficacy is limited in naïve pigs. Therefore, a safe and efficacious PEDV vaccine is still needed to control the disease. Previous pathogenicity studies between non-S INDEL and S INDEL isolates demonstrate S INDEL is less pathogenic while providing cross-protective neutralizing antibodies and might be a good candidate for modified live virus (MLV) vaccine. Further, much is described about virulence differences between the two isolates in neonatal conventional pigs, but little is known in older pigs. Resulting data can then provide guidance on selecting appropriate PEDV strain to induce antibody responses in different ages of pigs and on selecting PEDV strains for vaccine development. Therefore, the goal of this dissertation was to improve the understanding of antibody responses and virulence of PEDVs in weaned and older pigs and its implication in vaccine development. In the first study, we aimed to evaluate the efficacy of a naturally attenuated PEDV S INDEL strain as a vaccine candidate. The S INDEL isolate was safe in orally inoculated pregnant gilts but only protective in piglets against virulent virus challenge when replication occurred in the dam. In the second study, S INDEL and non-S INDEL strains were evaluated in weaned, grower, and finisher pigs. The virulence and antibody response were both pig-age and strain-dependent where younger pigs were more susceptible to PEDV infection and the non-S INDEL strain overall induced a greater humoral immune response. Therefore, the non-S INDEL appears to be a better choice for MLV vaccine development. The third study was inspired by importers of US pork voicing concerns about the infectivity of meat from PEDV positive hogs. We concluded pork muscle sampled from the previous PEDV study was not infectious. Finally, the last study characterized attenuation phenotypes and protection efficacy of cell-culture adapted PEDVs. Non-S INDEL PEDVs at lower passages (P7, P25, and P50) were still virulent, and viruses at P75 and P100 showed some evidence of attenuation but still induced severe diarrhea in neonatal piglets. Additional evaluation of higher passaged non-S INDEL virus showed that P200 virus was attenuated without causing apparent clinical signs in neonatal piglets and was able to provide successful protection against virulent challenge in piglets, making this isolate ideal for further vaccine development. In addition, comparisons of whole genome sequences and virulence phenotypes of these PEDVs at different cell culture passages identified some amino acid changes which may be associated with virus attenuation. In summary, information gained from this dissertation provides further understanding about humoral immune response and virulence in post-weaned pigs infected by different PEDVs, which provided guidance for selecting an appropriate strain for vaccine development. A cell culture adapted non-S INDEL isolate at passage 200 was attenuated and capable of providing protective immunity and appears to be a promising MLV vaccine candidate.
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