Newcastle disease is a highly contagious viral disease affecting all species of birds. The disease can vary from an asymptomatic infection to a highly fatal disease, depending on the virus strain and the host species. Newcastle disease has a worldwide distribution and is a major threat to the poultry industries of all countries. Based on the severity of the disease produced in chickens, Newcastle disease virus (NDV) strains are grouped into three main pathotypes: lentogenic (strains that do not usually cause disease in adult chickens), mesogenic (strains of intermediate virulence) and velogenic (strains that cause high mortality).
NDV is a member of the genus Rubulavirus in the family Paramyxoviridae. The genome of NDV is a non-segmented, single-stranded, negative-sense RNA of 15186 nucleotides (Krishnamurthy & Samal, 1998, J Gen Virol 79, 2419-2424; Phillips et al., 1998, Arch Virol 143, 1993-2002; de Leeuw and Peeters, 1999, J Gen Virol 80, 131-136). The genomic RNA contains six genes that encode the following proteins in the order of: the nucleocapsid protein (NP), phosphoprotein (P), matrix protein (M), fusion protein (F), haemagglutinin-neuraminidase (HN) and large polymerase protein (L). Two additional proteins, V and W, of unknown function are produced by RNA editing during P gene transcription (Steward et al., 1993, J Gen Virol 74, 2539-2547).
Three proteins, i.e. NP, P and L proteins, constitute the nucleocapsid. The genomic RNA is tightly bound by the NP protein and together with the P and L proteins form the functional nucleocapsid within which resides the viral transcriptive and replicative activities. The F and HN proteins form the external envelope spikes, where the HN glycoprotein is responsible for attachment of the virus to host cell receptors and the F glycoprotein mediates fusion of the viral envelope with the host cell plasma membrane thereby enabling penetration of the viral genome into the cytoplasm of the host cell. The HN and F proteins are the main targets for the immune response. The M protein forms the inner layer of the virion.
NDV follows the general scheme of transcription and replication of other non-segmented negative-strand RNA viruses. The polymerase enters the genome at a promoter in the 3′ extragenic leader region and proceeds along the entire length by a sequential stop-start mechanism during which the polymerase remains template bound and is guided by short consensus gene start (GS) and gene end (GE) signals. This generates a free leader RNA and six non-overlapping subgenomic mRNAs. The abundance of the various mRNAs decreases with increasing gene distance from the promoter. The genes are separated by short intergenic regions (1-47 nucleotides) which are not copied into the individual mRNAs. RNA replication occurs when the polymerase somehow switches to a read-through mode in which the transcription signals are ignored. This produces a complete encapsulated positive-sense replicative intermediate which serves as the template for progeny genomes.
Reverse-genetic techniques have been reported to recover negative-sense viruses from cloned cDNA (Conzelmann, 1996, J Gen Virol 77, 381-389). For NDV, reverse-genetic technology is currently available for avirulent strain LaSota (Römer-Oberdörfer et al., 1999, J Gen Virol 80, 2987-2995; Peeters et al., 1999, J Gen Virol 73, 5001-5009).
Infectious laryngotracheitis (ILT) is an acute respiratory disease of chickens that causes significant economic losses to poultry industry worldwide (Bagust et al., 2000, Rev Sci Tech 19, 483-492; Bagust, 1986, Avian Pathol 15, 581-595). The causative pathogen, ILTV, is a member of the genus Iltovirus in the family Herpesviridae (Bagust et al., 2000, supra; Fuchs et al., 2007, Vet Res 38, 261-279). Currently, live attenuated vaccines are used to control ILT infections. However, the live-attenuated vaccines are not satisfactory since they can revert to virulence after bird-to-bird passage (Guy et al., 1991, Avian Dis 35, 348-355) and can induce latent infections (Hughes et al., 1991, Arch Virol 121, 213-218). Several alternative strategies have been used to develop improved ILTV vaccines (Mauricio et al., 2013, Avian Pathol 42, 195-205). One of the strategies has been the creation of ILTV deletion mutants for use as attenuated live-virus vaccines (Mauricio et al., 2013, supra). Two of the concerns of using gene deleted ILTV vaccine are the establishment of latency and the possibility that the gene-deleted vaccine virus could become virulent after recombination with different attenuated vaccine used in the same region (Sang-Won et al, 2012, Science 337, 188; Henderson et al., 1991, Am J Vet Res 52, 820-825). All studies conducted to date suggest that a virus-vectored ILTV vaccine will be most effective for prevention and control of ILT (Tong et al., 2001, Avian pathol 30, 143-148; Sun et al., 2008, Avian Dis 52, 111-117; Vagnozzi et al., 2012, Avian Pathol 41, 21-31). A vectored-vaccine will be safe and not lead to reversion to virulence or establishment of latency. However, current live virus vectored vaccines against ILT have limitations (Mauricio et al., 2013, supra; Vagnozzi et al. 2012, supra): (i) route of administration to large number of one-day old chicks, (ii) effective delivery of vaccine antigen to the mucosal surface, (iii) production cost, and (iv) incomplete protection. Therefore, there is a need to evaluate additional viral vectors to deliver ILTV antigens to chickens.
USPTO Backgrounds
USPTO Backgrounds