Current vaccines do not provide sufficient levels of protection against divergent porcine reproductive and respiratory syndrome virus (PRRSV) strains circulating in the field, mainly due to the substantial variation of the viral genome. We describe here a novel approach to generate a PRRSV vaccine candidate that could confer unprecedented levels of heterologous protection against divergent PRRSV isolates. By using a set of 59 nonredundant, full-genome sequences of type 2 PRRSVs, a consensus genome (designated PRRSV-CON) was generated by aligning these 59 PRRSV full-genome sequences, followed by selecting the most common nucleotide found at each position of the alignment. Next, the synthetic PRRSV-CON strain was generated through the use of reverse genetics. PRRSV-CON replicates as efficiently as our prototype PRRSV strain FL12, both in vitro and in vivo. Importantly, when inoculated into pigs, PRRSV-CON confers significantly broader levels of heterologous protection than does wild-type PRRSV. Collectively, our data demonstrate that PRRSV-CON can serve as an excellent candidate for the development of a broadly protective PRRSV vaccine.
IMPORTANCEThe extraordinary genetic variation of RNA viruses poses a monumental challenge for the development of broadly protective vaccines against these viruses. To minimize the genetic dissimilarity between vaccine immunogens and contemporary circulating viruses, computational strategies have been developed for the generation of artificial immunogen sequences (so-called "centralized" sequences) that have equal genetic distances to the circulating viruses. Thus far, the generation of centralized vaccine immunogens has been carried out at the level of individual viral proteins. We expand this concept to PRRSV, a highly variable RNA virus, by creating a synthetic PRRSV strain based on a centralized PRRSV genome sequence. This study provides the first example of centralizing the whole genome of an RNA virus to improve vaccine coverage. This concept may be significant for the development of vaccines against genetically variable viruses that require active viral replication in order to achieve complete immune protection. P orcine reproductive and respiratory syndrome (PRRS) is widespread in most swine-producing countries worldwide, causing significant economic losses to swine producers. In the United States alone, the disease causes approximately $664 million in losses to American swine producers annually (1). Clinical signs of PRRS include reproductive failure in pregnant sows and respiratory diseases in young pigs. The causative agent of PRRS is a positive-sense, single-stranded RNA virus that belongs to the family Arteriviridae of the order Nidovirales and is referred to as porcine reproductive and respiratory syndrome virus (PRRSV) (2-4). The PRRSV genome is ϳ15 kb in length and encodes at least 22 different viral proteins (5). Several viral proteins have been shown to elicit humoral and/or cell-mediated immune responses in infected pigs, but none of those proteins have be...