Glycoproteins C and D of PRV Strain HB1201 Contribute Individually to the Escape From Bartha-K61 Vaccine-Induced Immunity

Abstract

The newly emerged pseudorabies virus (PRV) novel variants can escape from the immunity induced by the classical vaccine Bartha-K61. Here we investigated the underlying mechanisms by constructing chimeric mutants between epidemic strain HB1201 and the Bartha-K61 vaccine. Our analyses focused on three viral envelope glycoproteins, namely gB, gC, and gD, as they exhibit remarkable genetic variations and are also involved in induction of protective immunity. The corresponding genes were swapped reciprocally either individually or in combination by using CRISPR/Cas9 technology and homologous recombination. The rescued chimeric viruses exhibited differential sensitivity to neutralizing antibodies in vitro, and gC was found to be the major contributor to inefficient neutralization against HB1201 by anti-Bartha-K61 serum. When tested in the 4-week-piglet model, substitution with HB1201 gC enabled Bartha-K61 to induce a protective immunity against HB1201 at a high challenge dose of 10 7 TCID 50. Interestingly, despite a relatively lower cross-neutralization ability, the gD exchange also enabled Bartha-K61 to protect piglets from lethal challenge. In both cases, clinical signs and microscopic lesions were eased, and so was the viral tissue load with the exception of brain. A better protection could be achieved when both gC and gD were swapped in terms of reducing viral load in brain and virus-induced microscopic lesions. Thus, our studies not only revealed individual roles of gC and gD variations in the immune escape and also suggested a synergistic effect of both proteins on induction of protective immunity. These findings have important implications in novel vaccine development for PRV control in China.

The Attenuated Pseudorabies Virus Vaccine Strain Bartha K61: A Brief Review on the Knowledge Gathered during 60 Years of Research

“…Several reports show that Bartha K61-vaccinated animals in fact are still clinically protected against lethal challenges by several recent, highly virulent, Chinese strains including XJ5 and AH02LA [36][37][38]. A recent publication however reported mortality of two out of five Bartha-vaccinated pigs when challenged with the highly virulent strain HB1201 [39]. There appears to be a growing consensus that Bartha K61 may show reduced efficacy toward some recent Chinese PRV strains due to antigenic differences of these new strains, including, those in the immunogenic viral gC and gD glycoproteins [39].…”

“…A recent publication however reported mortality of two out of five Bartha-vaccinated pigs when challenged with the highly virulent strain HB1201 [39]. There appears to be a growing consensus that Bartha K61 may show reduced efficacy toward some recent Chinese PRV strains due to antigenic differences of these new strains, including, those in the immunogenic viral gC and gD glycoproteins [39]. More in-depth immunological research is required to fully understand the antigenic differences that may affect the protective effects of Bartha K61 against different PRV field strains.…”

“…Because of its safe and efficacious profile, the Bartha K61 vaccine has also been implemented as a vector for vaccination against more distantly related PRV strains or even other pathogens. For example, in an effort to efficiently vaccinate against the recently emerged and antigenically different PRV strains in China, research groups have tried to optimize the Bartha K61 vaccine by exchanging several of its immunogenic viral antigens (such as gB, gD, and gC) with those of the emerging Chinese strains [39]. Based on neutralization assays and small-scale vaccination experiments, these strategies seem justifiable, though more in-depth vaccination experiments are necessary to validate their usefulness [35,37].…”

Epizootic situation of Aujeszky’s disease within the territory of the Republic of Kazakhstan

“…MA in herbivorous animals was always connected to close contact with pigs on the pasture or while keeping different animal species and pigs within the same premises. ADV infection among sheep housed together with pigs was also described by Ren et al (2020).…”

A NanoLuc Luciferase Reporter Pseudorabies Virus for Live Imaging and Quantification of Viral Infection

“…The PRV variants shared 97.1-99.9% nucleotide (nt) and 96.6-99.5% amino acid (aa) homology with PRV reference strains, and they belonged to different clades (3). Mutation of glycoproteins C and D of PRV variants led to the escape from Bartha-K61 vaccineinduced immunity (5), so gE/gI/TK-deleted PRV variant strains as a substitute for Bartha-K61 vaccine were used in China to control PR at present. Except for the immunogenicity change, the pathogenicity of PRV variant strains enhanced compared with the classic strain in both pigs and mice; however, it is not clear about the mechanism of enhanced pathogenicity to its hosts (6).…”