Avian paramyxoviruses (APMV) are negative-sense, single-stranded RNA viruses from the genus Avulavirus of the family Paramyxoviridae that frequently infect many species of birds, including poultry and wild birds 1. There are at least 13 serotypes of avian paramyxoviruses 2,3, and more are likely to be discovered as virus surveillance is undertaken in new avian species. It is believed that wild birds are natural reservoirs of APMV since some of the viruses are adapted to specific hosts and produce little to no clinical disease or mortality in these species. Among viruses that have produced disease in wild birds are selected isolates from APMV-2, APMV-4, APMV-5, APMV-7 and APMV-9. However, because of the limited number of in-depth host range studies, in general very little is known about the potential of APMV to cause disease in wild birds. The most widely studied APMVs are from serotype 1 (APMV-1), also known as Newcastle disease virus (NDV), of which the virulent forms can cause up to 100% mortality in naïve susceptible birds. The majority of APMV-1 experimental studies have been performed in poultry species.
The NDV genome is composed of six genes that encode six structural proteins: nucleoprotein (NP), phosphoprotein (P), matrix (M), fusion (F), hemagglutinin-neuraminidase (HN) and the RNA polymerase (L) 4. F and HN are surface proteins involved in cell attachment and fusion, M is important in virion assembly; NP, P and L are involved in nucleic acid replication and transcription. As a results of RNA editing of the P gene, an additional non-structural protein (V), and possibly another (W), may be produced 5. V is involved in modulation of the host innate immune response; the function of W is unknown. The fusion protein cleavage site is the critical site responsible for virulence 6.
Newcastle disease (ND) is caused by infections of poultry with virulent forms of the virus (vNDV), which have become endemic in countries of Africa, Asia, the Middle East and the Americas. Virulent NDV isolates are defined as those that produce a value equal to or greater than 0.7 in the intracerebral pathogenicity index (ICPI) assay or contain multiple basic amino acids in the fusion protein cleavage site along with a phenylalanine in position 117 7. The amino acid sequence of the fusion protein that determines virulence starts at position 113; in virulent viruses it is normally: 113K/R-Q-K/R-R↓F117 8.
The USA classified all vNDV as select agents because of their potentially high economic impact 9, while member countries of the OIE are required to report infections of poultry with vNDV within 24 hours following their identification 7. Outbreaks in Europe, the United States and Australia occur as a result of importation of vNDV from endemic regions or from spillover from wild bird reservoirs. Newcastle disease has severe economic consequences for the poultry industry that are a result of containment measures and reduced production as well as costs related to preventive efforts such as biosecurity, vaccination and trade restrictions 8. Birds infected with vNDV present a wide range of clinical signs depending on many factors including the species, breed, age, immunity, nutrition, health status, and stress level of the host, among others.
Newcastle disease viruses of low virulence (loNDV) have fewer basic amino acids in the cleavage site motif and a leucine, instead of a phenylalanine, at position 117. These loNDV occasionally infect poultry as a result of spillover from wild birds and may cause respiratory disease that can become severe by secondary infections 10. Different loNDV genotypes circulate in wild birds worldwide and normally are not known to cause disease in healthy domestic poultry, except when they mutate from having a fusion cleavage site of low virulence to that of a vNDV 11-14.
Different diagnostic methods are used to detect NDV and to determine virulence 15,16. Viruses obtained from oropharyngeal or cloacal swabs or tissues are normally grown in specific-pathogen-free (SPF) embryonated chicken eggs (ECE). The isolated viruses are further confirmed to be NDV either with serum containing anti-NDV specific antibodies in the hemagglutination-inhibition (HI) assay, or by NDV specific primers and probes in real-time reverse transcription polymerase chain reaction (rRT-PCR) assays 17. All NDV isolates are known to replicate in ECE and the mean death time from minimal lethal dose (MDT/MLD) to kill the embryo normally correlates with the virulence of the virus in chickens 18. Viruses with a MDT of 60 hours or lower are normally considered highly virulent. Serologic assays such as ELISA are also used in diagnostic laboratories to assess antibody response following vaccination, but have limited value in surveillance and diagnosis because of the almost universal use of vaccines in domestic poultry and the lack of developed strategies for differentiating vaccinated from infected (DIVA) birds 8. In the US, two different US Department of Agriculture (USDA)-validated, rRT-PCR assays are used extensively to identify all APMV-1 viruses (matrix (M) gene assay) and to differentiate only virulent strains (fusion (F) gene assay), respectively 19. Even though rRT-PCR is used extensively because results can be obtained within a few hours, virus isolation (VI) coupled with HI is still the “gold standard” method for definitive diagnose. Furthermore, since real time PCR methods are based on the similarity of the used primers and probes to the tested viruses, both USDA-validated assays have limitations and do not always detect all NDV isolates, thus updated assays have been developed but are not yet validated by the USDA.
Newcastle disease virus isolates have been separated phylogenetically into two major groups designated as class I and class II 20. Several APMV-1 classification systems are available, however discrepancies among the systems have made comparisons between studies confusing and challenging. In 2012, a unified classification system based on the complete coding sequences of the fusion protein gene was proposed 21. This system provided objective criteria for classification of viruses based on phylogenetic analysis and measurements of genetic distances and is now widely accepted among NDV researchers. The availability of a reliable and objective classification tool resulted in identification of new genotypes and sub-genotypes during the following years. 22. Currently, viruses of class I genotype 1 segregate into three sub-genotypes 23. In most cases, these viruses cause subclinical infections in wild birds 12,24. Similarly, class II, genotype I isolates are usually isolated from wild birds, and all are of low virulence, except for one instance of a loNDV mutating to a vNDV after circulation in chickens in Australia in 1998 14. These viruses were eradicated and no longer exist in the wild. Viruses of class II, genotype II are primarily of low virulence 17, however, virulent forms of viruses of this genotype were common in outbreaks during the 1940s and 1950s. Nowadays, there are occasional isolations of virulent NDVs of this genotype in Egypt, India and China in what appear to be escapes from human activity 25. Genotypes III-IX and XI –XVIII only contain vNDV isolates 23. The later viruses are not widely distributed across the globe and appear to have more limited geographic distribution: XI (Madagascar), XIII (mainly Southwest Asia), XVI (North America) and XIV, XVII and XVIII (Africa). Genotypes V, VI, and VII are the predominant genotypes circulating worldwide and contain only virulent viruses. Genotype V viruses emerged in South and Central America in the 1970s and caused outbreaks in Europe that same year. These viruses also caused outbreaks in North America, in Florida (1971, 1993) and California (1971 to 2002) 26, are still circulating in Mexico and are found in Belize 27-32. Isolates from genotype VI are found in multiple species 33,34 and occasionally spill over into poultry. They are mostly associated with infections of pigeons and doves, and are the cause of the third ND panzootic that started in the early 1970s, spread worldwide and continues today 35,36. These pigeon isolates led to multiple ND outbreaks in United Kingdom in 1984 and in unvaccinated poultry in France and Sweden as recently as 2010 and 2011 36-38.
Genotype VII isolates are responsible for the fourth panzootic, which started in the late 1980s in Southeast Asia and quickly spread to Africa and Europe 8. In 2008, a genotype VII NDV, similar to what is endemic in Asia, was isolated in Venezuela, which is the first report of this genotype in South America 39. The recent, identification of sub-genotype VIIi provided evidence of the emergence of an additional (5th) panzootic and viruses of this group have been circulating and causing disease in poultry in Indonesia, Israel and Pakistan 22,23,40. They have also been isolated from poultry in Bulgaria, Georgia and Turkey 41 and, since 2012, have been recovered more often than genotype XIII isolates, which were the most commonly isolated genotype from 2009- 2011 in Pakistan 22. Genotype VIII circulated in South Africa and Singapore in the 1960s, and in Argentina, China and Malaysia through the 1980s, with the last isolation reported from a turkey in Italy in 1994 23,42. Many more isolates belonging to different genotypes have been isolated across the globe and their geographic distribution, pathogenesis and genetic characteristics has been recently comprehensively reviewed 23 and characterized in detail by our lab and others 21,22,33,34,43-51.
Although the most likely reservoir of vNDV appears to be vaccinated poultry populations with the ability to shed virus without showing signs of clinical disease,, there is evidence that wild birds may represent natural reservoirs of vNDV 52. Phylogenetically related vNDV of genotype V have been isolated from double-crested cormorants from 1975 through 2010 in the US 44,53-55, and these same strains have been implicated in earlier ND outbreaks in commercial free-range turkeys 56,57. In 2010, vNDV was recovered from clinically ill cormorants and seagulls in states in the northeastern USA and these isolates were genetically related to the vNDV recovered from cormorants in Minnesota in 2008. As mentioned above, virulent pigeon paramyxovirus-1 (PPMV-1) viruses were first isolated in 1981 in pigeons, and these isolates continue to circulate in feral birds of the Columbidae family worldwide, and infect poultry species on occasion 33,36,37, despite these being non-migratory species. Other vNDV isolates have been isolated sporadically from imported tropical bird species but it is not known if these wild birds are natural reservoirs of vNDV or if they were infected at quarantine stations prior to export 1.
Vaccination with live and/or inactivated NDV based vaccines is part of the accepted control strategy in countries in which vNDV is endemic and is the major preventive strategy in the USA. Vaccination prevents disease but normally is not sufficient to prevent viral replication in the mucosal tissue. Many studies have demonstrated that current inactivated and live vaccines prevent clinical disease and mortality but cannot prevent infection and subsequent viral shedding 58-63. The excretion of viruses from vaccinated animals normally occurs during the first week post infection with virulent virus and it is possible that secreted viruses may continue to circulate in other poorly vaccinated birds; however, the role of vaccines on the emergence of new variants is largely unstudied. As a result NDV strains that show evidence of antigenic drift have been isolated in Asia and in Mexico 32, suggesting that new disease control strategies are needed.
Since 1988 viral vectored vaccines (vaccinia virus, fowlpox virus, pigeon poxvirus, herpes virus of turkeys (HVT), Marek’s disease virus and adeno-associated virus) that express the NDV F and/or HN proteins have been tested as vaccines and shown to be protective; some of these are being commercialized 8. The most commonly-used vectored vaccines are recombinant HVT-based NDV vaccines, which have received some acceptance because they do not produce the respiratory disease in commercial poultry that may be seen with live NDV vaccination, and they can be administered in ovo 64. Fowlpox virus vectored vaccines have also shown to be effective; however, they are affected by maternal antibodies against the vector. One advantage of vectored recombinant vaccines is the possibility of implementing serological differentiation strategies [DIVA vaccines] 65.
The establishment of a reverse genetics system for NDV 66,67 is one of the most promising strategies in the area of NDV vaccine development because it takes advantage of the extensive experience with live NDV vaccination and the low cost of NDV production in eggs, combined with the possibility of genetically modifying the genome to enhance the induced immune response. Recombinant NDV (rNDV) viruses created by replacing the HN and/or F genes of lentogenic or mesogenic NDV isolates with those from vNDV isolates (with their cleavage sites altered to those from low virulence viruses) 61,68-70 have been developed. These recombinant viruses are capable of reducing viral shedding compared to traditional vaccines and provide similar safety profiles; however, they do not completely prevent replication and shedding of challenge viruses.
Contributed by: Kiril M. Dimitrov, Patti J. Miller and Claudio L. Afonso
(US National Poultry Research Center, Southeast Poultry Research Laboratory)
Copyright © 2016 Kiril M. Dimitrov, Patti J. Miller and Claudio L. Afonso
First posted: 12-Oct-2016
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