Abstract
Porcine circovirus type 2 (PCV2), the causative agent of a wasting disease in weanling piglets, has periodically evolved into several new subtypes since its discovery, indicating that the efficacy of current vaccines can be improved. Although a DNA virus, the mutation rates of PCV2 resemble RNA viruses. The hypothesis that recoding of selected serine and leucine codons in the PCV2b capsid gene could result in stop codons due to mutations occurring during viral replication and thus result in rapid attenuation was tested. Vaccination of weanling pigs with the suicidal vaccine constructs elicited strong virus-neutralizing antibody responses. Vaccination prevented lesions, body-weight loss, and viral replication on challenge with a heterologous PCV2d strain. The suicidal PCV2 vaccine construct was not detectable in the sera of vaccinated pigs at 14 days post-vaccination, indicating that the attenuated vaccine was very safe. Exposure of the modified virus to immune selection pressure with sub-neutralizing levels of antibodies resulted in 5 of the 22 target codons mutating to a stop signal. Thus, the described approach for the rapid attenuation of PCV2 was both effective and safe. It can be readily adapted to newly emerging viruses with high mutation rates to meet the current need for improved platforms for rapid-response vaccines.
Highlights
In the last few decades, the number of newly emerging or re-emerging viral infections has increased significantly
In this study, we demonstrate for the first time that recoding of serine and leucine codons can result in the rapid attenuation and suicidal replication of Porcine circovirus type 2 (PCV2), providing for an optimal blend of vaccine efficacy and safety
All serine and leucine codons within the selected sequence were modified as listed in Table 1 to increase the probability that mutations at the 2nd or 3rd positions of the codon that are accrued during vaccine viral replication in the host could result in a stop codon and suicidal replication (Figure 1, Table 1)
Summary
In the last few decades, the number of newly emerging or re-emerging viral infections has increased significantly. The highly mutable nature of pathogenic RNA viruses and the associated antigenic and genetic diversity is a long-standing challenge for effective vaccine development [1,2]. Achieving the optimal balance between safety and efficacy is a challenge in developing attenuated vaccines [1]. The long lead development time associated with conventional methods of viral attenuation and the knowledge of well-characterized virulence determinants being a pre-requisite for rational reverse genetics-based approaches hinder rapid-response vaccine development for emerging viruses [1,2]. We have previously demonstrated that a minimally replicative vaccine against an enteric swine coronavirus [3] is highly effective at priming the immune system but is quickly eliminated from the vaccinated host. Minimally replicative vaccines can provide a much-desired amalgamation of vaccine safety and efficacy properties
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