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Journal of Virology, December 2001, p. 11868-11873, Vol. 75, No. 23
Department of Microbiology, Mount Sinai
School of Medicine, New York, New York 10029,1
and Department of Biochemistry and Molecular Biology,
University of Salamanca, Salamanca, Spain2
Received 4 May 2001/Accepted 4 September 2001
A complete cDNA clone of the Newcastle disease virus (NDV) vaccine
strain Hitchner B1 was constructed, and infectious recombinant virus
expressing an influenza virus hemagglutinin was generated by reverse
genetics. The rescued virus induces a strong humoral antibody response
against influenza virus and provides complete protection against a
lethal dose of influenza virus challenge in mice, demonstrating the
potential of recombinant NDV as a vaccine vector.
Newcastle disease virus (NDV) is a
member of the Rubulavirus genus in the
Paramyxoviridae family and is categorized into three pathotypes depending on the severity of the disease that it
causes in birds: lentogenic, mesogenic, or velogenic (1,
33). The ability to genetically engineer negative-strand RNA
viruses has led to extraordinary advances in understanding their
biology. The first reports of NDV rescue from cDNA were published in
1999 (22, 28). Both groups used the lentogenic NDV strain
LaSota. Recently, this strain was further attenuated by modifying the RNA editing site in the P gene, which resulted in low-level expression of the V protein (18). In addition, the generation of a
chimeric recombinant NDV containing a hybrid HN gene with the
N-terminal region derived from NDV and the external C-terminal region
from avian paramyxovirus type 4 was reported (23).
Finally, Krishnamurthy et al. (15) and Huang et al.
(11) rescued recombinant NDVs (mesogenic strain Beaudette
C and lentogenic strain LaSota, respectively) stably expressing the
chloramphenicol acetyltransferase (CAT) reporter gene.
An important application of reverse-genetic techniques is the
generation of recombinant viruses for use as vaccine vectors (reviewed
in references 4, 8, 19, 21, and 26). A number of recombinant negative-strand RNA viruses expressing foreign proteins
have been constructed. Recombinant vesicular stomatitis viruses (VSVs)
are able to express the human CD4 protein (32), the
influenza virus hemagglutinin (HA) and neuraminidase (14, 25,
27), the respiratory syncytial virus G and F proteins (12), the human immunodeficiency virus Gag and Env
proteins (10), and the bovine viral diarrhea virus E2
protein (9). Their efficacies as vaccine vectors have been
studied (reviewed in reference 26). Among paramyxoviruses,
several chimeric measles viruses and Sendai viruses expressing foreign
genes have been constructed (29, 35, 38), and a rinderpest
virus expressing an influenza virus HA protein has been described
(37). The latter recombinant was shown to induce humoral
immunity in vaccinated cattle (37). In this paper, a
recombinant NDV expressing the HA protein of influenza A virus was
generated from the full-length cDNA of the avirulent strain Hitchner B1
(ATCC VR108), a widely used NDV live vaccine strain. The potential of
the recombinant NDV as an effective vaccine vector was evaluated.
Rescue of recombinant viruses from cloned cDNAs.
pNDV/B1,
containing the full-length cDNA of the Hitchner B1 strain was
constructed (Fig. 1), and two additional
restriction enzyme sites (SacII, nucleotides
[nt] 1755 to 1760; and XbaI, nt 3163 to 3168) were
created as genetic tag sequences. The complete genome (15,186 nt) of
pNDV/B1 was sequenced using a model ABI 3700 sequencer
(Applied Biosystems). We chose the newly introduced XbaI
site, located between the P and M genes to insert the CAT gene
(24) or the HA gene of influenza A/WSN/33 virus
(7). These constructs (pNDV/B1-CAT and pNDV/B1-HA) should
retain the normal ratio of NP to P expression, which appears to be
critical for effective viral replication (2). The numbers
of the inserted nucleotides in pNDV/B1-CAT and pNDV/B1-HA were 696 and
1,752, respectively, maintaining the genome length as a
multiple of 6 (3). To generate recombinant NDVs from
pNDV/B1, pNDV/B1-CAT, and pNDV/B1-HA, HEp-2 or A549 cells in a six-well
plate were infected with MVA-T7 (kindly provided by B. Moss)
at a multiplicity of infection of 1 and then transfected with each NDV
full-length clone (1 µg) together with the following expression
plasmids: pTM1-NP (nucleoprotein) at 0.4 µg, pTM1-P (phosphoprotein)
at 0.2 µg, and pTM1-L (RNA-dependent RNA polymerase) at 0.2 µg.
After overnight incubation, the transfected cells were cocultured with chicken embryo fibroblasts (CEF) to amplify the produced virus and then
incubated for an additional 2 to 3 days. The supernatants of
transfected cells were injected into the allantoic cavities of 9- or
10-day-old embryonated chicken eggs. Three to four days later,
allantoic fluids were harvested and virus growth was confirmed by
hemagglutination assays followed by hemagglutination inhibition (HI)
testing. Viral genomic RNAs were isolated from the rescued viruses
(rNDV/B1, rNDV/B1-CAT, and rNDV/B1-HA) and the tagged restriction
enzyme sites, and the presence of the inserted foreign genes was
confirmed by reverse transcription-PCR-restriction enzyme digestion analysis (data not shown).
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.23.11868-11873.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Recombinant Newcastle Disease Virus as a
Vaccine Vector
ABSTRACT
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FIG. 1.
Schematic representation of pNDV/B1, pNDV/B1-CAT, and
pNDV/B1-HA cDNA constructs. (A) pNDV/B1 was generated by seven PCR
fragments spanning the following nucleotide positions: F1, T7 promoter,
nt 1755 (SacII); F2, nt 1 to 3321; F3, nt 1755 (SacII) to 6580; F4, nt 6151 to 10,210; F5, nt 7381 to
11,351; F6, nt 11,351 to 14,995; and F7, nt 14,701 to 15,186. These
sequences were followed by the hepatitis delta virus (HDV)
ribozyme and the T7 terminator. The cDNA fragments were joined at
shared restriction sites and assembled in plasmid pSL1180 (Amersham
Pharmacia Biotech). SacII and XbaI are
shown in italics to indicate that they are genomic tag sequences. (B)
The pNDV/B1-CAT and pNDV/B1-HA constructs were made by inserting the
CAT and influenza virus A/WSN/33 HA open reading frames (ORF),
respectively, into the unique XbaI cloning site (nt
3163) located between the P and M genes of the pNDV/B1 clone. The
inserted gene contains the gene end (GE; 5'-TTAGAAAAAA-3'),
intercistronic nucleotide (T), and the gene start sequence (GS;
5'-ACGGGTAGAA-3'). In addition, seven nucleotides
(5'-CGCCACC-3') were inserted upstream of the initiation
site to introduce an optimal Kozak sequence (13). In the
case of pNDV/B1-HA, the gene start sequence is followed by the 5'
untranslated region (26 nt) of the HA gene.
rNDV/B1-HA virus stably expresses HA protein on the cell
surface.
The expression of HA protein was analyzed by infection of
35-mm-diameter dishes of confluent CEF cells with either rNDV/B1 or rNDV/B1-HA at a multiplicity of infection of 1. Cells were fixed at
1 and 2 days postinfection using 1% paraformaldehyde. NDV proteins and
HA protein were visualized using a mouse anti-NDV polyclonal serum and
a monoclonal antibody (2G9) against influenza virus HA, respectively,
followed by incubation with peroxidase-conjugated anti-mouse
immunoglobulins (Boehringer Mannheim). Extensive cytopathic effects and
typical syncytia were observed in cells infected with rNDV/B1 or
rNDV/B1-HA at 2 days postinfection (Fig.
2A, images a, b, c, e, f, and g) but not
in mock-infected cells (Fig. 2A, images d and h). NDV infection was
demonstrated by staining with an anti-NDV serum (Fig. 2A, images a, b,
and c). In contrast, the HA-specific monoclonal antibody (2G9) reacted
only with rNDV/B1-HA-infected cells and not with rNDV/B1- or
mock-infected cells (Fig. 2A, images e, f, g, and h). These results
suggested that the HA protein is efficiently expressed and transferred
to the cell surfaces of rNDV/B1-HA-infected cells. A similar result was
reported for recombinant VSV and rinderpest virus expressing the HA
protein (14, 37). In addition, we demonstrated that the HA
protein was stably expressed from rNDV/B1-HA following 10 passages in
embryonated eggs at a low multiplicity of infection (10 to 100 PFU/egg)
(Fig. 2A, image g). The stable expression of a foreign gene was also
confirmed using rNDV/B1-CAT. CAT expression was not changed after 10 passages in embryonated eggs at a low multiplicity of infection (data
not shown).
|
HA incorporation into virions. Previous studies showed that the HA protein expressed from recombinant VSV was efficiently incorporated into virions (14). On the other hand, recombinant rinderpest virus did not incorporate the expressed HA protein into particles (37). Thus, we wished to determine whether the HA protein was incorporated into the virions of the recombinant NDV. For this purpose, virions of rNDV/B1-HA, rNDV/B1, or influenza A/WSN/33 virus were purified and concentrated using a two-step centrifugation method (7,000 × g for 30 min and 200, 000 × g for 90 min over a 30% sucrose cushion). The total amount of protein in purified virus preparations was measured using a Bradford assay kit (Bio-Rad). Viral proteins were electrophoresed on a sodium dodecyl sulfate-10% polyacrylamide gel, followed by immunoblotting with anti-HA monoclonal antibodies (H15-A13, B-8, B-9, B-15, B-17, C-10, C-12, and E-10, kindly provided by W. Gerhard). The result showed that the amount of HA protein in the rNDV/B1-HA virion was four- to eightfold lower than that in influenza A/WSN/33 virus, assuming that the same number of viral particles per microgram of viral proteins was present (Fig. 2B). The HA protein incorporated into rNDV/B1-HA particles appeared to be cleaved, indicating that the HA protein was accessible to proteolytic enzymes.
Virus growth kinetics and pathogenicity of rNDV/B1-HA.
Embryonated chicken eggs were inoculated with the parent virus
(wild-type NDV/B1 [wtNDV/B1]), rNDV/B1, rNDV/B1-CAT, or rNDV/B1-HA at
100 PFU per egg. Viral growth was analyzed at different time points
after inoculation. A 50% tissue culture infective dose (TCID50) of each virus was determined by
immunofluorescence assay. Ninety-six well plates of 80%-confluent CEF
were infected with serial 10-fold dilutions of virus (four wells per
dilution). Cells were incubated for 2 days and fixed with 2.5%
formaldehyde containing 0.1% Triton X-100. Viral proteins were
visualized using an anti-NDV rabbit serum followed by fluorescein
isothiocyanate-conjugated anti-rabbit immunoglobulins (DAKO). wtNDV/B1,
rNDV/B1, and rNDV/B1-CAT grew to similar titers
(109 TCID50/ml), whereas
the maximal viral titer achieved with rNDV/B1-HA was approximately
20-fold lower (5 × 107
TCID50/ml) (Fig.
3). In order to test the virulence of
rNDV/B1-HA, the mean time of death in eggs was determined. Serial
10-fold dilutions of infectious allantoic fluid
(10
6 to 108) of
wtNDV/B1, rNDV/B1, and rNDV/B1-HA viruses were inoculated into each of
five embryonated eggs and the mean time in hours for the minimal lethal
dose to kill embryos was determined. Embryos inoculated with the
wtNDV/B1 and rNDV/B1 viruses died within 6 days. The mean times of
death of the wild-type virus and rNDV/B1 were 108 and 113 h,
respectively. In contrast, approximately 80% of embryos inoculated
with rNDV/B1-HA survived beyond 8 days postinoculation. Similar results
were obtained if higher amounts of viruses (103
to 105 dilutions) were inoculated. These
results indicate that rNDV/B1-HA is attenuated in embryonated chicken
eggs. Since NDV Hitchner B1 is routinely used to vaccinate poultry,
rNDV/B1 expressing an avian influenza virus HA could be used as a
vaccine against avian influenza viruses as well as NDV.
|
Immnunogenicity and pathogenicity of recombinant NDV in mice.
We demonstrated that rNDV/B1-HA efficiently expresses the HA
protein on the surfaces of infected cells and that a significant amount
of HA molecules is associated with the virus (Fig. 2). We next
attempted to use this rNDV/B1-HA as a vaccine vector to protect mice
against challenge with influenza virus. Previous studies showed that
recombinant VSV and recombinant rinderpest virus expressing the HA
protein induced a humoral antibody responses in vivo (25, 27,
37). BALB/c mice were inoculated with rNDV/B1-HA either
intravenously or intraperitoneally at 3 × 107 PFU per
mouse. Phosphate-buffered saline (PBS) or the same amount of rNDV/B1
was administered intravenously as a control. No weight loss was
observed in mice inoculated with rNDV/B1-HA or with rNDV/B1 (data not
shown). Although growth levels of these viruses in mice were not
determined, the lack of weight loss suggests that rNDV/B1 and
rNDV/B1-HA have little or no toxicity in mice. Mice inoculated with
rNDV/B1 or rNDV/B1-HA showed no measurable antibody response to either
NDV or influenza virus 14 days after the initial inoculation (data not
shown). One week after being given a booster injection (28 days after
the initial inoculation), an antibody response against NDV was induced
in mice inoculated with rNDV/B1 or rNDV/B1-HA by intravenous
administration (Table 1). HI antibody
titers against NDV in the two groups were similar (Table 1).
Intraperitoneal administration of rNDV/B1-HA also induced a significant
anti-NDV antibody response, but the HI titers were lower than those
after the intravenous administration. As expected, specific
anti-influenza virus antibody was detected only in mice inoculated with
rNDV/B1-HA. Intravenous administration induced higher titers of
antibody to influenza virus HA than intraperitoneal
administration (Table 1).
|
Efficacy of recombinant NDV in generating protective immunity.
On day 35 after the initial inoculation (2 weeks after the booster
injection), mice were challenged with 105 PFU
(100 50% lethal doses [LD50]) of influenza
A/WSN/33 virus by intranasal administration. As shown in Fig.
4 and Table 1, rNDV/B1-HA-immunized mice
were protected against a lethal dose of influenza virus. In the case of
intraperitoneal administration, although detectable weight loss was
observed at first, mice fully recovered within 10 days (Fig. 4). In
addition, no changes in physical activity and fur appearance were
observed after influenza virus challenge in any of the vaccinated mice.
In contrast, control mice inoculated with rNDV/B1 or PBS were not
protected and died within 7 days of the influenza virus challenge (Fig.
4 and Table 1). Previous studies (6, 36) found that
protection is related to HA antibody induction, and our investigation
is consistent with these findings (Table 1). Little is known about the
replication of lentogenic NDV in mice. Analysis of the growth kinetics
and tissue distribution of NDV/B1 in mammalian animals remains to be
done. However, it has been demonstrated that virulent NDV replicates in
mice (17). Also, certain NDV strains (including pathogenic and avirulent strains) have been shown to possess oncolytic activity (reviewed in reference 34) and, most importantly, it has been reported
that NDV can infect humans without inducing severe symptoms (5,
20, 30). Clinical trials using NDV as an antitumor agent have
shown encouraging preliminary results for patients with a variety of
cancers, and phase III trials are beginning in Europe
(20). These results indicate the potential of using recombinant NDVs in humans. Recombinant NDVs expressing components of
other human pathogens might be able to induce, without severe side
effects, a protective immune response to these agents. A recombinant
NDV-based vaccine against human immunodeficiency virus may thus be
envisioned. In addition, NDV-infected cells have been shown to produce
cytokines such as interferons and tumor necrosis factor, stimulating
immune responses (16, 31, 34). This immune
response-stimulatory activity of NDV may be the reason for the finding
that patients developed a highly immunogenic response to their own
tumor following administration of X-ray-irradiated NDV-infected
autologous tumor cells (reviewed in reference 30).
|
) or intraperitoneally (i.p.) (
), with rNDV/B1 intravenously
(
), or with PBS (
) are shown. The vaccinating dose was 3 × 107 PFU/ml in all cases. The error bars indicate ±0.5
times the standard deviation.
Nucleotide sequence accession number. The complete genome (15,186 nt) of pNDV/B1 was submitted to GenBank under accession number AF375823.
| |
ACKNOWLEDGMENTS |
|---|
This work was partially supported by grants to A.G.-S. from the National Institutes of Health, by grants to P.P. from the National Institutes of Health, and by a grant to E.V. from the Direccion General de Ensenanza Superior of Spain (DGES PM97/0160). Y.N. was supported by an Uehara Memorial Bio-Medical Research Foundation fellowship.
A mixture of monoclonal antibodies to the influenza A/WSN/33 virus HA was kindly provided by Walter Gerhard. pTM1 and MVA-T7 were kindly provided by Bernard Moss.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Department of Microbiology, Mount Sinai School of Medicine, One Gustave Levy Pl., New York, NY 10029. Phone for Peter Palese: (212) 241-7318. Fax: (212) 722-3634. E-mail: peter.palese{at}mssm.edu. Phone for Adolfo García-Sastre: (212) 241-7769. Fax: (212) 534-1684. E-mail: adolfo.garcia-sastre{at}mssm.edu.
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Journal of Virology, December 2001, p. 11868-11873, Vol. 75, No. 23
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.23.11868-11873.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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(2008). Influenza B Virus NS1-Truncated Mutants: Live-Attenuated Vaccine Approach. J. Virol.
82: 10580-10590
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Ge, J., Deng, G., Wen, Z., Tian, G., Wang, Y., Shi, J., Wang, X., Li, Y., Hu, S., Jiang, Y., Yang, C., Yu, K., Bu, Z., Chen, H.
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Wang, S., Taaffe, J., Parker, C., Solorzano, A., Cao, H., Garcia-Sastre, A., Lu, S.
(2006). Hemagglutinin (HA) Proteins from H1 and H3 Serotypes of Influenza A Viruses Require Different Antigen Designs for the Induction of Optimal Protective Antibody Responses as Studied by Codon-Optimized HA DNA Vaccines. J. Virol.
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Bukreyev, A., Skiadopoulos, M. H., Murphy, B. R., Collins, P. L.
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Park, M.-S., Steel, J., Garcia-Sastre, A., Swayne, D., Palese, P.
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(2006). A Single Intranasal Inoculation with a Paramyxovirus-Vectored Vaccine Protects Guinea Pigs against a Lethal-Dose Ebola Virus Challenge. J. Virol.
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