Development of a broadly protective modified-live virus vaccine candidate against porcine reproductive and respiratory syndrome virus

Authors: SUN, HAIYAN - University Of Nebraska; Workman, Aspen; OSORIO, FERNANDO - University Of Nebraska; STEFFEN, DAVID - University Of Nebraska; VU, HIEP - University Of Nebraska

Submitted to: Vaccine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/13/2017
Publication Date: 11/22/2017
Publication URL: http://handle.nal.usda.gov/10113/5870005
Citation: Sun, H., Workman, A., Osorio, F.A., Steffen, D., Vu, H.L.X. 2017. Development of a broadly protective modified-live virus vaccine candidate against porcine reproductive and respiratory syndrome virus. Vaccine. 36:66-73. https://doi.org/10.1016/j.vaccine.2017.11.028.
DOI: https://doi.org/10.1016/j.vaccine.2017.11.028

Interpretive Summary: Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of an important viral disease of swine. There are at least three PRRSV modified-live virus (MLV) vaccines available in the U.S. market; however, swine producers are not satisfied with the efficacy of these vaccines. The main limitation of current PRRSV vaccines is that they do not confer sufficient levels of protection against the wide range of PRRSV strains currently circulating in the field. The extensive genetic diversity among PRRSV isolates is the main factor that accounts for the failure of the current PRRSV vaccines to confer broad protection. To minimize the genetic dissimilarity between vaccine strains and contemporary circulating viruses, computational strategies have been developed for the generation of artificial PRRSV sequences (so-called “centralized” sequences) that have equal genetic distances to the circulating viruses in the field. This synthetic virus (designated CON-P1) was shown previously to provide unprecedented levels of protection against divergent strains of the virus. However, because it was designed from field strains of the virus, it caused disease in pigs and was not suitable to be used as a vaccine. In this study, we attenuated CON-P1 by continuously passaging the virus in a non-natural host cell line. As the virus adapted to replicating in the non-natural host cell line, it became attenuated (it caused less severe disease in pigs). It was shown the attenuated virus (CON-P90) retained similar levels of protection against divergent field strains of the virus, making it an excellent candidate for the formulation of next generation PRRSV MLV vaccines with improved levels of protection against the array of circulating field strains.

Technical Abstract: Modified-live virus (MLV) vaccines are widely used to protect pigs against porcine reproductive and respiratory syndrome virus (PRRSV). However, current MLV vaccines do not confer adequate levels of heterologous protection, presumably due to the substantial genetic diversity of PRRSV isolates circulating in the field. To overcome this genetic variation challenge, we recently generated a synthetic PRRSV strain containing a consensus genomic sequence of PRRSV-2. We demonstrated that our synthetic PRRSV strain confers unprecedented levels of heterologous protection. However, the synthetic PRRSV strain at passage 1 (hereafter designated CON-P1) is highly virulent and therefore, is not suitable to be used as a vaccine in pigs. In the present study, we attenuated CON-P1 by continuously passaging the virus in MARC-145 cells, a non-natural host cell line. Using a young pig model, we demonstrated that the synthetic virus at passages 90 and 122 (designated as CON-P90 and CON-P122, respectively) were fully attenuated, as evidenced by the significantly reduced viral loads in serum and tissues and the absence of lung lesion in the infected pigs. Most importantly, CON-P90 confers similar levels of heterologous protection as its parental strain CON-P1. Taken together, the results indicate that CON-P90 is an excellent candidate for the formulation of next generation of PRRSV MLV vaccines with improved levels of heterologous protection.