Single-Dose Vaccination of a Recombinant Parainfluenza Virus 5 Expressing NP from H5N1 Virus Provides Broad Immunity against Influenza A Viruses

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and may be good candidates for vaccine development. In this study, we examined immunity induced by rMuV⌬SH and rMuV⌬V in mice. Furthermore, we generated recombinant mumps viruses lacking expression of both the V protein and the SH protein (rMuV⌬SH⌬V). Analysis of rMuV⌬SH⌬V indicated that it was stable in tissue culture cell lines. Importantly, rMuV⌬SH⌬V was immunogenic in mice, indicating that it is a promising candidate for mumps vaccine development. Mumps is a human infectious disease characterized by lateral or bilateral nonsuppurative swelling of the parotid glands. In severe cases, mumps can lead to orchitis in postpuberty male patients and damage to the central nervous system. In the prevaccine era, 90% of the population turned seropositive for mumps virus (MuV) by 14 to 15 years of age, reflecting its highly contagious nature. Mumps virus is neurotropic and was one of the most common causes of aseptic meningitis before the implementation of mass mumps vaccination programs.At present, the Jeryl Lynn (JL) vaccine is the most commonly used mumps vaccine, administered as lyophilized live virus with measles and rubella vaccine components. The JL vaccine strain originated from an infectious isolate from a mumps patient in 1963 (1). The virus was attenuated through continuous passages in embryonic hen eggs and chicken embryos/chicken embryo cell cultures (1). The JL vaccine was licensed in the United States in 1967 and has been used for over 40 years. This vaccine has been efficacious and safe overall (2-6). However, several large mumps outbreaks have occurred recently in the United States and worldwide in populations that have been vaccinated with the JL vaccine (7-10). Major mumps outbreaks in the United States include the 2006 multistate mumps outbreak, reporting 6,584 suspected cases originating from the state of Iowa (11, 12) and the 2009 -2010 New York and New Jersey mumps outbreaks with a total of 2,078 suspected cases reported in 2010 (13). Both of the outbreaks occurred among highly vaccinated populations, raising questions about the efficacy of the current vaccination program in the United States. One possible causality is the antigenic differences between the genotype A vaccine strain and the genotype G circulating wild-type mumps viruses.In this study, we seek to develop a mumps vaccine candidate through genetic modification of a clinically isolated mumps virus. Mumps virus is a member of the family Paramyxoviridae, subfamily Paramyxovirinae, and genus Rubulavirus (6,14). It is an enveloped virus enclosing a negative-sense, single-stranded, nonsegmented RNA genome of 15,384 nucleotides in length which encodes 9 viral proteins (15-17). Studies of the function of the Paramyxovirus SH protein reveal that it blocks tumor necrosis factor alpha (TNF-␣) induction, signaling, caspase activation, and NF-B nuclear translocation in transfected and virus-infected cells (18)(19)(20)(21)(22)(23). The V protein is an accessory protein translated from the authentic transcript of the V/P gene (24,25). Mumps V protein...

Section: Discussionsupporting

confidence: 60%

Immunogenicity of Novel Mumps Vaccine Candidates Generated by Genetic Modification

Chen

Phan

et al. 2014

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“…The development of an influenza vaccine providing broadly cross-protective immunity will be of great advantage. Recently, PIV5-based influenza virus vaccines have been generated and found to be highly effective in animals (10)(11)(12). In the present study, the efficacy of a PIV5-based vaccine was further improved by modifying the PIV5 vector.…”

Section: Discussionmentioning

confidence: 65%

“…Fourth, in recent studies, a single dose of a live recombinant PIV5 expressing the HA gene (rPIV5-H5) from the highly pathogenic avian influenza (HPAI) virus H5N1 subtype provided sterilizing immunity against a lethal dose of influenza A virus H5N1 infection in mice (10,11). PIV5 expressing NP, an internal protein of influenza virus, protected against lethal influenza virus challenge in mice, as well (12). The levels of protection afforded by PIV5-based H5N1 vaccine candidates in mice are unprecedented.…”

mentioning

confidence: 99%

Efficacy of Parainfluenza Virus 5 Mutants Expressing Hemagglutinin from H5N1 Influenza A Virus in Mice

Gabbard

Mooney

et al. 2013

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Parainfluenza virus 5 (PIV5) is a promising viral vector for vaccine development. PIV5 is safe, stable, efficacious, cost-effective to produce and, most interestingly, it overcomes preexisting antivector immunity. We have recently reported that PIV5 expressing the hemagglutinin (HA) from highly pathogenic avian influenza (HPAI) virus H5N1 (PIV5-H5) provides sterilizing immunity against lethal doses of HPAI H5N1 infection in mice. It is thought that induction of apoptosis can lead to enhanced antigen presentation. Previously, we have shown that deleting the SH gene and the conserved C terminus of the V gene in PIV5 results in mutant viruses (PIV5⌬SH and PIV5V⌬C) that enhance induction of apoptosis. In this study, we inserted the HA gene of H5N1 into PIV5⌬SH (PIV5⌬SH-H5) or PIV5V⌬C (PIV5V⌬C-H5) and compared their efficacies as vaccine candidates to PIV5-H5. We have found that PIV5⌬SH-H5 induced the highest levels of anti-HA antibodies, the strongest T cell responses, and the best protection against an H5N1 lethal challenge in mice. These results suggest that PIV5⌬SH is a better vaccine vector than wild-type PIV5.

“…PIV5 can infect humans and animals without causing any known symptoms or diseases (3,4). It has been used as a vector for vaccine development (5)(6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Regulation of Viral RNA Synthesis by the V Protein of Parainfluenza Virus 5

Yang

Zengel

Sun

et al. 2015

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Paramyxoviruses include many important animal and human pathogens. The genome of parainfluenza virus 5 (PIV5), a prototypical paramyxovirus, encodes a V protein that inhibits viral RNA synthesis. In this work, the mechanism of inhibition was investigated. Using mutational analysis and a minigenome system, we identified regions in the N and C termini of the V protein that inhibit viral RNA synthesis: one at the very N terminus of V and the second at the C terminus of V. Furthermore, we determined that residues L16 and I17 are critical for the inhibitory function of the N-terminal region of the V protein. IMPORTANCEWe identified two regions of the V protein that interact with NP and determined that one of these regions enhances viral RNA transcription via its interaction with NP. Our data suggest that a common host factor may be involved in the regulation of paramyxovirus replication and could be a target for broad antiviral drug development. Understanding the regulation of paramyxovirus replication will enable the rational design of vaccines and potential antiviral drugs. The family Paramyxoviridae belongs to the Mononegavirales and has two subfamilies, the Paramyxovirinae and the Pneumovirinae. The subfamily Paramyxovirinae contains five genera: Rubulavirus, Respirovirus, Morbillivirus, Avulavirus, and Henipavirus. The subfamily Pneumovirinae contains two genera: Pneumovirus and Metapneumovirus. This virus family includes many wellknown human and animal pathogens, such as mumps virus (MuV), which belongs to the genus Rubulavirus; Sendai virus (SeV) and human parainfluenza virus 3 (PIV3), which belong to the genus Respirovirus; measles virus (MV), which belongs to the genus Morbillivirus; and emerging viruses like Nipah virus (NiV), which belongs to the genus Henipavirus (1). Parainfluenza virus 5 (PIV5), formerly known as simian virus 5 (SV5) (2), is a prototypical paramyxovirus and belongs to the Rubulavirus genus in the Paramyxoviridae family. PIV5 can infect humans and animals without causing any known symptoms or diseases (3, 4). It has been used as a vector for vaccine development (5-11).The PIV5 genome consists of a nonsegmented negativestranded RNA which is encapsidated by the nucleocapsid (NP) protein (1). The viral RNA polymerase (vRNAP) complex that contains the large (L) protein and the phosphoprotein (P) transcribes the NP-encapsidated genome RNA into 5=-capped and 3=-polyadenylated mRNAs. vRNAP starts viral RNA synthesis at the 3= end of the genome, and it transcribes the genes into mRNAs in a sequential (and polar) manner by terminating and reinitiating transcription at each of the gene junctions (1). vRNAP also replicates the RNA genome by making an exact copy of the genome from negative-sense RNA to positive-sense RNA and from positive-sense RNA back to negative-sense RNA. Viral RNA transcription occurs first after infection to allow the production of viral proteins, and viral RNA replication follows (1). PIV5 is an enveloped virus and enters the cell by fusing with the plasma mem-