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Journal of Virology, November 2001, p. 10498-10504, Vol. 75, No. 21
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10498-10504.2001
A Chimeric Human-Bovine Parainfluenza Virus Type 3 Expressing Measles Virus Hemagglutinin Is Attenuated for Replication
but Is Still Immunogenic in Rhesus Monkeys
Mario H.
Skiadopoulos,*
Sonja R.
Surman,
Jeffrey M.
Riggs,
Peter L.
Collins, and
Brian R.
Murphy
Respiratory Viruses Section, Laboratory of
Infectious Diseases, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Maryland 20892
Received 28 March 2001/Accepted 30 July 2001
 |
ABSTRACT |
The chimeric recombinant virus rHPIV3-NB, a version of
human parainfluenza virus type 3 (HPIV3) that is attenuated due to the
presence of the bovine PIV3 nucleocapsid (N) protein open reading frame
(ORF) in place of the HPIV3 ORF, was modified to encode the measles
virus hemagglutinin (HA) inserted as an additional, supernumerary gene
between the HPIV3 P and M genes. This recombinant, designated
rHPIV3-NBHA, replicated like its attenuated
rHPIV3-NB parent virus in vitro and in the upper and lower
respiratory tracts of rhesus monkeys, indicating that the insertion of
the measles virus HA did not further attenuate rHPIV3-NB in
vitro or in vivo. Monkeys immunized with rHPIV3-NBHA
developed a vigorous immune response to both measles virus and HPIV3,
with serum antibody titers to both measles virus (neutralizing
antibody) and HPIV3 (hemagglutination inhibiting antibody) of over
1:500. An attenuated HPIV3 expressing a major protective antigen of
measles virus provides a method for immunization against measles by the
intranasal route, a route that has been shown with HPIV3 and
respiratory syncytial virus vaccines to be relatively refractory to the
neutralizing and immunosuppressive effects of maternally derived
virus-specific serum antibodies. It should now be possible to induce a
protective immune response against measles virus in 6-month-old
infants, an age group that in developing areas of the world is not
responsive to the current measles virus vaccine.
| |
TEXT |
Measles virus is a member of
the genus Morbillivirus of the Paramyxoviridae
family of viruses (20). Measles virus infection causes the
death of over 1 million children per year and remains among the most
important causes of mortality due to infectious disease worldwide
(27). A measles virus vaccine is available, but it is
largely ineffective in infants under 9 to 15 months of age because
maternally acquired measles virus-specific antibodies readily
neutralize this parenterally administered attenuated vaccine virus
(1). Since measles virus causes serious illness in infants 6 to 15 months of age (45), there is a need for a measles
virus vaccine that can induce a protective immune response in infants possessing maternally acquired measles virus antibodies. Human parainfluenza virus type 3 (HPIV3) is another important human pathogen
and is second only to respiratory syncytial virus as a cause of serious
pediatric viral respiratory tract disease worldwide (7).
Several approaches to the development of vaccines to protect the very
young infant against PIV3 or measles virus infection have been pursued
(9, 14, 32, 42, 43, 54, 55). Virus vectors carrying a
major antigenic determinant of HPIV3 (12, 53) or measles
virus (11, 15, 36, 38, 44, 49, 50) have shown promise but
are not always effective in the presence of serum antibodies to PIV3
(12) or measles virus (54), which are present
in young infants as maternally derived serum immunoglobulin G. A live
attenuated vaccine that is delivered directly into the respiratory
tract, where it replicates and induces both a systemic and a mucosal
antibody response, can effectively circumvent the neutralizing activity
of serum antibody (12, 52).
Some of the most promising paramyxovirus vaccine candidates are live
attenuated viruses, since these have been shown to be highly
efficacious in nonhuman primates even in the presence of high levels of
passively transferred antibodies, an experimental situation that
simulates that of the very young infant with maternally acquired
antibodies (8, 12). For HPIV3, two candidate vaccines have
been shown in clinical trials to be well tolerated, safe, and
immunogenic in infants and children, namely (i) the cold-passaged (cp)
HPIV3 cp45 virus, which contains a number of attenuating point
mutations, and (ii) the Kansas (Ka) strain of bovine PIV3 (BPIV3),
which is attenuated by a host range restriction (see below) (22,
26). Because of these successful clinical experiences, we have
been exploring the use of attenuated PIV3 as a vector to express
antigens of additional pathogens for the purpose of designing bivalent
or multivalent pediatric vaccines. We previously constructed a version
of HPIV3, termed rcp45L (HA P-M)
(14), that expressed measles virus hemagglutinin (HA) from
an added gene and contained three cp45-derived attenuating point
mutations in the L gene (39).
rcp45L (HA P-M) was attenuated and
immunogenic for both HPIV3 and measles virus in hamsters.
The strategy of using an animal virus that is attenuated in humans
because of a host range restriction as a vaccine against a virulent
antigenically related human virus represents the "Jennerian" approach to vaccine development (31). BPIV3 was found to
be 100- to 1,000-fold restricted in replication in rhesus monkeys compared to wild-type (wt) HPIV3 (6). However, BPIV3 is
only 25% antigenically related to HPIV3 in cross-neutralization assays (6) and is therefore not optimally immunogenic for HPIV3.
We previously constructed a viable chimeric recombinant bovine-human PIV3 containing the nucleoprotein (N) open reading frame (ORF) from
BPIV3 Ka in place of the HPIV3 N ORF, previously designated cKa-N
(3) and referred to here as
rHPIV3-NB. This virus was restricted in
replication in rhesus monkeys to the same extent as its BPIV3 parent
virus (3). Furthermore, this identified the BPIV3 N
protein as a major determinant for the host range restriction of
replication of BPIV3 in primates. rHPIV3-NB
induced a high level of resistance in rhesus monkeys to challenge with the biologically derived wt JS strain of HPIV3. The
rHPIV3-NB chimeric virus thus combines the
antigenic determinants of wt HPIV3 with the host range restriction and
attenuation phenotype of BPIV3. There are 79 differences out of a total
of 515 amino acids between the N proteins of HPIV3 and BPIV3
(4). Many of these 79 amino acid differences likely
contribute to the host range attenuation phenotype of
rHPIV3-NB. Because the host range restriction of
BPIV3 is expected to be based on numerous amino acid differences, it is
anticipated that the attenuation phenotype of
rHPIV3-NB will be stable even following prolonged
replication in vivo. In the present study, we evaluated
rHPIV3-NB as a vector for the expression of
measles virus HA for the purpose of developing a bivalent vaccine for
intranasal (IN) immunization of infants and young children.
Construction, recovery, and in vitro growth characteristics of
rHPIV3-NBHA.
The antigenomic cDNA encoding
rHPIV3-NB (3) was modified to
contain the measles virus HA ORF inserted as an additional gene between
the P and M genes (Fig. 1). The source of
the HA gene was a previously constructed wt HPIV3 antigenomic cDNA,
pFLC(HA P-M) (14), containing the HA ORF under the control
of HPIV3 gene start and gene end transcription signals and inserted as a supernumerary gene into the wt rHPIV3 genome between the P and M
genes. We replaced the PshAI-to-XhoI fragment of
the rHPIV3-NB antigenomic cDNA with that of
pFLC(HA P-M) bearing the HA gene. Recombinant virus, designated
rHPIV3-NBHA, was readily recovered from HEp-2
cells transfected with the chimeric antigenomic cDNA and support
plasmids and was biologically cloned and propagated on LLC-MK2 cells as
described previously (42). Viral RNA was isolated from the
recovered virus, and the added HA gene and flanking sequences were
amplified by reverse transcription-PCR and were analyzed by
restriction enzyme digestion and nucleotide sequencing. This confirmed
that the genome structure of the recovered
rHPIV3-NBHA virus was exactly as designed (data
not shown).
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FIG. 1.
Schematic diagram (not to scale) of the parent and
chimeric PIV3s. The relative positions of the BPIV3 N ORF ( ; shaded
regions consist of BPIV3 sequence) and measles virus HA ORF
( ) are indicated in biologically derived and recombinant PIV3s. The
restriction sites used to transfer the HA gene into
rHPIV3-NBHA are shown.
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|
The kinetics of replication in vitro of
rHPIV3-N
BHA was compared to that of its
rHPIV3-N
B parent and wt rHPIV3 by infecting
LLC-MK2 cells at a multiplicity of infection of 0.01 and measuring
the
virus yield at 24-h intervals, as described previously
(
42).
rHPIV3-N
BHA displayed a rate
of growth similar to that of rHPIV3-N
B and also
grew to a peak titer on day 4 similar to that of each
of its parent
viruses (Fig.
2). This demonstrated that
the insertion
of an additional gene into the chimeric PIV3 genome did
not attenuate
this virus for replication in vitro.
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FIG. 2.
Multistep growth curves of rHPIV3s. LLC-MK2 monolayers
were infected in triplicate with the indicated rPIV3 at a multiplicity
of infection of 0.01 at 32°C. Aliquots of the medium supernatants
were harvested at 24-h intervals and were assayed at 32°C for virus
titer. Virus titers are expressed as mean log10
TCID50 per milliliter ± SE.
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|
The expression of the measles virus HA was initially examined by
immunostaining plaques formed on LLC-MK2 monolayer cultures
infected
with rHPIV3-N
BHA with mouse monoclonal antibodies
specific
to the measles virus HA or with monoclonal antibodies specific
for the HPIV3 hemagglutinin-neuraminidase (HN) protein as described
previously (
14). The viral titers determined by
immunostaining
rHPIV3-N
BHA plaques on monolayer
cultures with a mixture of measles
HA- or HPIV3 HN-specific antibodies
were essentially indistinguishable,
indicating that the HA antigen was
expressed by the majority of
plaque-forming virions (data not shown).
Expression of the measles
virus gene was also confirmed by indirect
immunofluorescence of
LLC-MK2 cells infected with
rHPIV3-N
BHA (Fig.
3). LLC-MK2 cells
grown on glass slides
were infected with a recombinant HPIV3 or
with wt HPIV1. Approximately
44 h postinfection, the cells were
fixed and permeabilized as
described previously (
40). Mouse
monoclonal anti-HPIV3
(101/1 and 454/11 [
47]) (Fig.
3A) or anti-measles
HA
antibodies (79-XV-V17, 80-III-B2, and 81-1-366 [a gift of Stephen
Jacobson, National Institutes of Health] [
14]) (Fig.
3B) and
fluorescein isothyocianate-conjugated anti-mouse immunoglobulin
G antibodies (Jackson Immunochemicals, West Grove, Pa.) were
used
for detection of the HPIV3 HN or measles virus HA glycoprotein,
respectively. The pattern of fluorescence in cells infected with
rHPIV3-N
BHA demonstrated that this recombinant
expressed the major
antigenic determinants of both HPIV3 and measles
virus. Both viral
glycoproteins localized to the cell membrane and to
the cytoplasm.
Efficient expression of the measles virus HA in vivo was
confirmed
as described below.
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FIG. 3.
rHPIV3-NBHA expresses the major antigenic
determinants of HPIV3 and measles virus. Mouse monoclonal anti-HPIV3 HN
(101/1 and 454/11) (A) and mouse monoclonal anti-measles HA antibodies
(79-XV-V17, 80-III-B2, and 81-1-366) (B) were used to detect the HN
protein and HA in LLC-MK2 cells infected with the indicated virus.
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rHPIV3-NBHA replicates to the same level as
rHPIV3-NB in the respiratory tracts of rhesus monkeys.
Rhesus macaques are permissive for HPIV3 (13) and measles
virus (34) replication and are, therefore, appropriate
animal models for the study of PIV or measles virus infection and
immunity. This nonhuman primate model has been used to screen PIV
vaccine candidates before proceeding to clinical trials
(23). We sought to determine if the presence of the
measles virus HA significantly decreased the replication of
rHPIV3-NB in the upper and lower respiratory
tracts of immunized nonhuman primates, as had been previously observed
in a rodent model when a supernumerary gene was inserted into an
attenuated HPIV3 backbone (14, 41). We also sought to
determine if rHPIV3-NBHA replicated sufficiently to induce a satisfactory immune response against both HPIV3 and measles
virus in nonhuman primates, a more appropriate animal model than
rodents for these human pathogens. The replication of
rHPIV3-NBHA in the
upper and lower respiratory tracts of rhesus monkeys was compared to
that of its rHPIV3-NB parent as well as to that of wt rHPIV3 and wt BPIV3 (Table 1). Rhesus monkeys
that were seronegative for both HPIV3 and measles virus were inoculated simultaneously by the IN and intratracheal (IT) routes with 1 ml of L15
medium per site containing 105 50% tissue
culture infective doses (TCID50) of virus, as
described previously (3, 37). Nasopharyngeal (NP) swab
samples were collected on days 1 through 10 postinfection, and tracheal
lavage (TL) samples were collected on days 2, 4, 6, 8, and 10 postinfection. Virus present in the NP and TL specimens was quantified
by titration on LLC-MK2 cell monolayers at 32°C, as previously
described (42), and the mean peak virus titer obtained was
expressed as log10 TCID50
per milliliter (Table 1). Table 1 also includes data collected from
similarly infected and sampled rhesus monkeys from two previous studies
(3, 37).
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TABLE 1.
rHPIV3-NBHA, a chimeric human-bovine PIV3
expressing the measles virus HA gene, is satisfactorily attenuated for
replication in the upper and lower respiratory tracts of rhesus
monkeys, induces antibodies to both HPIV3 and measles virus, and
protects against HPIV3 wt virus challenge
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|
The rHPIV3-N
BHA chimeric virus replicated in the
upper and lower respiratory tracts of rhesus monkeys to a level
comparable
to that of its rHPIV3-N
B parent virus.
rHPIV3-N
BHA was significantly
restricted in
replication in the upper respiratory tract compared
to rHPIV3 wt
(
P < 0.05; Student's
t test), but the
level of replication
of rHPIV3 wt in the lower respiratory tract is
low, precluding
meaningful statistical comparison. The level of
replication of
rHPIV3-N
BHA was also comparable to
that of the BPIV3 candidate
vaccine, demonstrating that
rHPIV3-N
B HA retains the host range
attenuation
phenotype of rHPIV3-N
B and BPIV3. This also
indicated
that, unexpectedly, the insertion of the measles virus HA
gene
into the rHPIV3-N
B genome did not
significantly further attenuate
this virus for replication in the
respiratory tracts of rhesus
monkeys. This suggests that the
attenuation conferred by inserting
the HA ORF between the PIV3 P and M
genes previously observed
in hamsters (
14) may be specific
to that animal model or is
largely masked in primates by the
attenuation phenotype specified
by the bovine N gene
product.
Immunization of rhesus monkeys with rHPIV3-NBHA induced
high titers of antibodies against both HPIV3 and measles virus and
protected the monkeys from challenge with biologically derived
HPIV3.
Although cell-mediated immunity likely plays a role in
protection against PIV and measles virus disease, the sparing of severe measles virus infection in early infancy defines a major role for
antibodies in resistance to disease caused by measles virus. Previously, it was found that hamsters immunized with a recombinant HPIV3 expressing the measles virus HA developed high serum neutralizing antibody titers to measles virus (14). However, it was not
known if a strong immune response to a vectored antigen could be
induced in primates, a more appropriate model for a human viral
pathogen. As shown in Table 1, rhesus monkeys immunized with
rHPIV3-NBHA developed a high level of serum
antibodies against both HPIV3 and measles virus. Serum HPIV3 antibodies
were quantified by hemagglutination inhibition (HAI) assay using guinea
pig erythrocytes as described previously (48), and the
titers are expressed as mean reciprocal log2 ± standard error (SE). A high level of serum HAI antibodies to HPIV3 was
induced by both rHPIV3-NBHA (1:128) and
rHPIV3-NB (1:181), demonstrating that these
attenuated recombinants can induce a strong immune response against the
backbone antigens of the HPIV3 vector. The serum neutralizing antibody
titer against measles virus was quantified by plaque assay as described
previously (14), and the titer is expressed as reciprocal
mean log2 ± SE (Table 1). Rhesus monkeys
immunized with rHPIV3-NBHA developed a high level
of measles virus neutralizing antibodies of 1:588 (1,661 mIU)
measured 31 days after immunization, a level that is in substantial
excess of that needed to protect humans against infection with measles
virus (5, 28).
To compare the efficacy of immunization with the live attenuated
rHPIV3-N
BHA and rHPIV3-N
B
virus vaccine candidates against
wt HPIV3 infection, the monkeys were
challenged IN and IT with
10
6
TCID
50 of the biologically derived JS strain of
wt HPIV3 31 days
after immunization (Table
1). NP swab and TL samples
were collected
on days 2, 4, 6, and 8 postchallenge. Virus present in
the specimens
was quantified by serial dilution on LLC-MK2 monolayer
cultures
as described above. rHPIV3-N
BHA and
rHPIV3-N
B induced comparable
high levels of
protection against challenge with wt HPIV3, as
indicated by a 100- to
1,000-fold reduction in wt HPIV3 replication
in the respiratory tract
of immunized monkeys. This demonstrated
that insertion of the measles
virus HA gene into the chimeric
bovine-human PIV3 did not diminish the
level of protection induced
by the HPIV3 glycoproteins present in the
backbone of the attenuated
vector.
We next sought to compare the immunogenicity of
rHPIV3-N
BHA with that of the live attenuated
Moraten strain measles virus
vaccine in rhesus monkeys. Rhesus monkeys
previously infected
with rHPIV3 (
n = 2),
rHPIV3-N
B (
n = 2), or
rHPIV3-N
BHA (
n = 4)
were
immunized parenterally (intramuscularly) with 10
5
PFU of the Moraten virus on day 59, and serum samples were collected
on
day 87 and analyzed for neutralizing antibodies against measles
virus
(Table
1). In measles virus-naive animals (Table
1, groups
1 and
2), the titer of measles virus-specific antibodies induced
by the
Moraten vaccine virus was similar to that observed in
rHPIV3-N
BHA-immunized
animals (Table
1, group 3).
Thus, the immunogenicity of the rHPIV3-N
BHA
vector expressing the HA glycoprotein of measles virus was equivalent
to that of the Moraten measles vaccine virus. This demonstrates
that an
attenuated PIV3 can be used as a vector to construct a
multivalent
vaccine to immunize primates against multiple human
viral
pathogens.
An important advantage of a PIV vector-based vaccine for measles virus
over the licensed Moraten vaccine is that the PIV vector
can be
administered by the IN route, whereas live-attenuated measles
virus
vaccines are not consistently infectious by this route,
probably as a
consequence of their attenuation and adaptation
to cell culture
(
10). This makes it possible to immunize with
rHPIV3-N
BHA in early infancy, an age group that
cannot be immunized
with a current live attenuated measles virus
vaccine such as the
Moraten strain because the vaccine virus is
neutralized by passively
acquired maternal antibodies
(
14). Replication of respiratory
viruses in the upper
respiratory tract is relatively refractory
to an inhibitory effect of
passively transferred serum antibodies
(
35). Therefore, it
was not surprising to find that the HPIV3
and respiratory syncytial
virus live attenuated vaccine candidates
are infectious and immunogenic
in experimental animals which have
been administered physiologic
amounts of virus-neutralizing antibodies
as well as in infants and
young children possessing maternally
derived virus-specific serum
antibodies (
8,
12,
24,
25,
52). It is reasonable to expect
that the same will be true of
heterologous antigens borne by
recombinant HPIV3. This will be
investigated directly in future studies
by examining the safety
and protective efficacy of
rHPIV3-N
BHA in rhesus monkeys that
have received
passive infusion of physiologic amounts of antibodies
specific to
HPIV3, measles virus, or both. In addition, the local
antibody response
and the longevity of the serum immune response
to the vectored measles
antigen will be examined in future studies
to determine if prior
immunization with a PIV-measles recombinant
interferes with subsequent
immunization with the Moraten vaccine
strain.
The lack of effective vaccination against measles virus infection
results in the death of over 2,700 children every day worldwide
(
51). The rHPIV3-N
BHA candidate
vaccine offers a unique opportunity
to immunize against two major
causes of severe pediatric disease,
namely, HPIV3 and measles virus.
Unlike the currently licensed
measles virus vaccines, we expect that
chimeric rHPIV3-N
BHA, expressing
the major
antigenic determinant of measles virus, can be used
to induce a strong
immune response to measles virus in infants
about 6 months of age
(
14). Additional chimeric recombinant
PIVs expressing the
measles virus F glycoprotein with or without
HA will also be generated,
and their immunogenicity and efficacy
will be examined in animal
models. The need for a measles virus
vaccine to protect children less
than 15 months of age is greatest
in the regions of the world where
there also is a high prevalence
of infection with human
immunodeficiency virus (
30,
33). The
candidate measles
vaccine described here should be phenotypically
stable in vivo
following prolonged replication in an immunocompromised
host because
the attenuation phenotype is likely specified by
many of the 79 amino
acid differences that differentiate the bovine
and human N proteins,
but this assumption requires experimental
verification. We are further
examining the basis of attenuation
of the bovine N gene in
rHPIV3-N
B and its phenotypic stability
following
prolonged replication in a permissive host. An effective
immunization
strategy for infants and children will be required
to meet the World
Health Organization goal to eradicate measles
by the year 2010. In
particular, it would be advantageous in the
final stage of measles
eradication to employ a vaccine that does
not involve infectious
measles virus, thereby precluding possible
persistence of the pathogen,
as may occur in immunocompromised
individuals, and reversion to the wt
phenotype seen with other
live attenuated virus vaccines (
2,
16-19,
21,
29,
46).
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ACKNOWLEDGMENTS |
We thank Robert Chanock, Jason Newman, and Lea Vogel for reviewing
the manuscript. We also thank Judy Beeler for the standardized measles
serum and Ernest Williams and Fatemeh Davoodi for technical assistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Room 100, Building 7, NIH, 7 Center Dr. MSC 0720, Bethesda, MD 20892-0720. Phone: (301) 594-2271. Fax: (301) 496-8312. E-mail:
mskiadopoulos{at}niaid.nih.gov.
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REFERENCES |
| 1.
|
Albrecht, P.,
F. A. Ennis,
E. J. Saltzman, and S. Krugman.
1977.
Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure.
J. Pediatr.
91:715-718[CrossRef][Medline].
|
| 2.
|
Anonymous.
2000.
Outbreak of poliomyelitis Dominican Republic and Haiti, 2000.
Morb. Mortal. Wkly. Rep.
49:1094-1103[Medline].
|
| 3.
|
Bailly, J. E.,
J. M. McAuliffe,
A. P. Durbin,
W. R. Elkins,
P. L. Collins, and B. R. Murphy.
2000.
A recombinant human parainfluenza virus type 3 (PIV3) in which the nucleocapsid N protein has been replaced by that of bovine PIV3 is attenuated in primates.
J. Virol.
74:3188-3195[Abstract/Free Full Text].
|
| 4.
|
Bailly, J. E.,
J. M. McAuliffe,
M. H. Skiadopoulos,
P. L. Collins, and B. R. Murphy.
2000.
Sequence determination and molecular analysis of two strains of bovine parainfluenza virus type 3 that are attenuated for primates.
Virus Genes
20:173-182[CrossRef][Medline].
|
| 5.
|
Chen, R. T.,
L. E. Markowitz,
P. Albrecht,
J. A. Stewart,
L. M. Mofenson,
S. R. Preblud, and W. A. Orenstein.
1990.
Measles antibody: reevaluation of protective titers.
J. Infect. Dis.
162:1036-1042[Medline].
|
| 6.
|
Coelingh, K.,
C. C. Winter,
E. L. Tierney,
W. T. London, and B. R. Murphy.
1988.
Attenuation of bovine parainfluenza virus type 3 in nonhuman primates and its ability to confer immunity to human parainfluenza virus type 3 challenge.
J. Infect. Dis.
157:655-662[Medline].
|
| 7.
|
Collins, P. L.,
R. M. Chanock, and K. McIntosh.
1996.
Parainfluenza viruses, p. 1205-1243.
In
B. N. Fields, D. M. Knipe, P. M. Howley, R. M. Chanock, J. L. Melnick, T. P. Monath, B. Roizman, and S. E. Straus (ed.), Fields virology, 3rd ed., vol. 1. Lippincott-Raven Publishers, Philadelphia, Pa.
|
| 8.
|
Crowe, J. E., Jr.,
P. T. Bui,
G. R. Siber,
W. R. Elkins,
R. M. Chanock, and B. R. Murphy.
1995.
Cold-passaged, temperature-sensitive mutants of human respiratory syncytial virus (RSV) are highly attenuated, immunogenic, and protective in seronegative chimpanzees, even when RSV antibodies are infused shortly before immunization.
Vaccine
13:847-855[CrossRef][Medline].
|
| 9.
|
Crowe, J. E., Jr.,
P. L. Collins,
R. M. Chanock, and B. R. Murphy.
1997.
Vaccines against respiratory syncytial virus and parainfluenza virus type 3, p. 711-725.
In
M. M. Levine, G. C. Woodrow, J. B. Kaper, and G. S. Cobon (ed.), New generation vaccines, 2nd ed. Marcel Dekker, Inc, New York, N.Y.
|
| 10.
|
Cutts, F. T.,
C. J. Clements, and J. V. Bennett.
1997.
Alternative routes of measles immunization: a review.
Biologicals
25:323-338[CrossRef][Medline].
|
| 11.
|
Drillien, R.,
D. Spehner,
A. Kirn,
P. Giraudon,
R. Buckland,
F. Wild, and J. P. Lecocq.
1988.
Protection of mice from fatal measles encephalitis by vaccination with vaccinia virus recombinants encoding either the hemagglutinin or the fusion protein.
Proc. Natl. Acad. Sci. USA
85:1252-1256[Abstract/Free Full Text].
|
| 12.
|
Durbin, A. P.,
C. J. Cho,
W. R. Elkins,
L. S. Wyatt,
B. Moss, and B. R. Murphy.
1999.
Comparison of the immunogenicity and efficacy of a replication-defective vaccinia virus expressing antigens of human parainfluenza virus type 3 (HPIV3) with those of a live attenuated HPIV3 vaccine candidate in rhesus monkeys passively immunized with PIV3 antibodies.
J. Infect. Dis.
179:1345-1351[CrossRef][Medline].
|
| 13.
|
Durbin, A. P.,
W. R. Elkins, and B. R. Murphy.
2000.
African green monkeys provide a useful nonhuman primate model for the study of human parainfluenza virus types-1, -2, and -3 infection.
Vaccine
18:2462-2469[CrossRef][Medline].
|
| 14.
|
Durbin, A. P.,
M. H. Skiadopoulos,
J. M. McAuliffe,
J. M. Riggs,
S. R. Surman,
P. L. Collins, and B. R. Murphy.
2000.
Human parainfluenza virus type 3 (PIV3) expressing the hemagglutinin protein of measles virus provides a potential method for immunization against measles virus and PIV3 in early infancy.
J. Virol.
74:6821-6831[Abstract/Free Full Text].
|
| 15.
|
Fooks, A. R.,
E. Schadeck,
U. G. Liebert,
A. B. Dowsett,
B. K. Rima,
M. Steward,
J. R. Stephenson, and G. W. Wilkinson.
1995.
High-level expression of the measles virus nucleocapsid protein by using a replication-deficient adenovirus vector: induction of an MHC-1-restricted CTL response and protection in a murine model.
Virology
210:456-465[CrossRef][Medline].
|
| 16.
|
Friedrich, F.
2000.
Molecular evolution of oral poliovirus vaccine strains during multiplication in humans and possible implications for global eradication of poliovirus.
Acta Virol.
44:109-117[Medline].
|
| 17.
|
Furione, M.,
S. Guillot,
D. Otelea,
J. Balanant,
A. Candrea, and R. Crainic.
1993.
Polioviruses with natural recombinant genomes isolated from vaccine-associated paralytic poliomyelitis.
Virology
196:199-208[CrossRef][Medline].
|
| 18.
|
Georgescu, M. M.,
J. Balanant,
A. Macadam,
D. Otelea,
M. Combiescu,
A. A. Combiescu,
R. Crainic, and F. Delpeyroux.
1997.
Evolution of the Sabin type 1 poliovirus in humans: characterization of strains isolated from patients with vaccine-associated paralytic poliomyelitis.
J. Virol.
71:7758-7768[Abstract].
|
| 19.
|
Greensfelder, L.
2000.
Infectious diseases. Polio outbreak raises questions about vaccine.
Science
290:1867-1869.
|
| 20.
|
Griffin, D. E., and W. J. Bellini.
1996.
Measles virus, p. 1267-1312.
In
B. N. Fields, D. M. Knipe, P. M. Howley, R. M. Chanock, J. L. Melnick, T. P. Monath, B. Roizman, and S. E. Straus (ed.), Fields virology, vol. 1. Lippincott-Raven Publishers, Philadelphia, Pa.
|
| 21.
|
Guillot, S.,
V. Caro,
N. Cuervo,
E. Korotkova,
M. Combiescu,
A. Persu,
A. Aubert-Combiescu,
F. Delpeyroux, and R. Crainic.
2000.
Natural genetic exchanges between vaccine and wild poliovirus strains in humans.
J. Virol.
74:8434-8443[Abstract/Free Full Text].
|
| 22.
|
Hall, S. L.,
C. M. Sarris,
E. L. Tierney,
W. T. London, and B. R. Murphy.
1993.
A cold-adapted mutant of parainfluenza virus type 3 is attenuated and protective in chimpanzees.
J. Infect. Dis.
167:958-962[Medline].
|
| 23.
|
Hall, S. L.,
A. Stokes,
E. L. Tierney,
W. T. London,
R. B. Belshe,
F. C. Newman, and B. R. Murphy.
1992.
Cold-passaged human parainfluenza type 3 viruses contain ts and non-ts mutations leading to attenuation in rhesus monkeys.
Virus Res.
22:173-184[CrossRef][Medline].
|
| 24.
|
Karron, R. A.,
M. Makhene,
K. Gay,
M. H. Wilson,
M. L. Clements, and B. R. Murphy.
1996.
Evaluation of a live attenuated bovine parainfluenza type 3 vaccine in two- to six-month-old infants.
Pediatr. Infect. Dis. J.
15:650-654[CrossRef][Medline].
|
| 25.
|
Karron, R. A.,
P. F. Wright,
S. L. Hall,
M. Makhene,
J. Thompson,
B. A. Burns,
S. Tollefson,
M. C. Steinhoff,
M. H. Wilson,
D. O. Harris, et al.
1995.
A live attenuated bovine parainfluenza virus type 3 vaccine is safe, infectious, immunogenic, and phenotypically stable in infants and children.
J. Infect. Dis.
171:1107-1114[Medline].
|
| 26.
|
Karron, R. A.,
P. F. Wright,
F. K. Newman,
M. Makhene,
J. Thompson,
R. Samorodin,
M. H. Wilson,
E. L. Anderson,
M. L. Clements,
B. R. Murphy, and R. B. Belshe.
1995.
A live human parainfluenza type 3 virus vaccine is attenuated and immunogenic in healthy infants and children.
J. Infect. Dis.
172:1445-1450[Medline].
|
| 27.
|
Katz, S. L., and B. G. Gellin.
1994.
Measles vaccine: do we need new vaccines or new programs?
Science
265:1391-1392[Free Full Text].
|
| 28.
|
Lee, M. S.,
D. J. Nokes,
H. M. Hsu, and C. F. Lu.
2000.
Protective titres of measles neutralising antibody.
J. Med. Virol.
62:511-517[CrossRef][Medline].
|
| 29.
|
Martin, J.,
G. L. Ferguson,
D. J. Wood, and P. D. Minor.
2000.
The vaccine origin of the 1968 epidemic of type 3 poliomyelitis in Poland.
Virology
278:42-49[CrossRef][Medline].
|
| 30.
|
Moss, W. J.,
F. Cutts, and D. E. Griffin.
1999.
Implications of the human immunodeficiency virus epidemic for control and eradication of measles.
Clin. Infect. Dis.
29:106-112[Medline].
|
| 31.
|
Murphy, B. R., and R. M. Chanock.
1996.
Immunization against virus disease, p. 467-498.
In
B. N. Fields, D. M. Knipe, P. M. Howley, R. M. Chanock, J. L. Melnick, T. P. Monath, B. Roizman, and S. E. Straus (ed.), Fields virology, 3rd ed., vol. 1. Lippincott-Raven, Philadelphia, Pa.
|
| 32.
|
Osterhaus, A.,
G. van Amerongen, and R. van Binnendijk.
1998.
Vaccine strategies to overcome maternal antibody mediated inhibition of measles vaccine.
Vaccine
16:1479-1481[CrossRef][Medline].
|
| 33.
|
Perry, R. T.,
F. Mmiro,
C. Ndugwa, and R. D. Semba.
2000.
Measles infection in HIV-infected African infants.
Ann. N. Y. Acad. Sci.
918:377-380[Medline].
|
| 34.
|
Polack, F. P.,
P. G. Auwaerter,
S. H. Lee,
H. C. Nousari,
A. Valsamakis,
K. M. Leiferman,
A. Diwan,
R. J. Adams, and D. E. Griffin.
1999.
Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody.
Nat. Med.
5:629-634[CrossRef][Medline].
|
| 35.
|
Prince, G. A.,
R. L. Horswood, and R. M. Chanock.
1985.
Quantitative aspects of passive immunity to respiratory syncytial virus infection in infant cotton rats.
J. Virol.
55:517-520[Abstract/Free Full Text].
|
| 36.
|
Schlereth, B.,
J. K. Rose,
L. Buonocore,
V. ter Meulen, and S. Niewiesk.
2000.
Successful vaccine-induced seroconversion by single-dose immunization in the presence of measles virus-specific maternal antibodies.
J. Virol.
74:4652-4657[Abstract/Free Full Text].
|
| 37.
|
Schmidt, A. C.,
J. M. McAuliffe,
A. Huang,
S. R. Surman,
J. E. Bailly,
W. R. Elkins,
P. L. Collins,
B. R. Murphy, and M. H. Skiadopoulos.
2000.
Bovine parainfluenza virus type 3 (BPIV3) fusion and hemagglutinin-neuraminidase glycoproteins make an important contribution to the restricted replication of BPIV3 in primates.
J. Virol.
74:8922-8929[Abstract/Free Full Text].
|
| 38.
|
Schnell, M. J.,
L. Buonocore,
E. Kretzschmar,
E. Johnson, and J. K. Rose.
1996.
Foreign glycoproteins expressed from recombinant vesicular stomatitis viruses are incorporated efficiently into virus particles.
Proc. Natl. Acad. Sci. USA
93:11359-11365[Abstract/Free Full Text].
|
| 39.
|
Skiadopoulos, M. H.,
A. P. Durbin,
J. M. Tatem,
S. L. Wu,
M. Paschalis,
T. Tao,
P. L. Collins, and B. R. Murphy.
1998.
Three amino acid substitutions in the L protein of the human parainfluenza virus type 3 cp45 live attenuated vaccine candidate contribute to its temperature-sensitive and attenuation phenotypes.
J. Virol.
72:1762-1768[Abstract/Free Full Text].
|
| 40.
|
Skiadopoulos, M. H., and A. A. McBride.
1996.
The bovine papillomavirus type 1 E2 transactivator and repressor proteins use different nuclear localization signals.
J. Virol.
70:1117-1124[Abstract].
|
| 41.
|
Skiadopoulos, M. H.,
S. R. Surman,
A. P. Durbin,
P. L. Collins, and B. R. Murphy.
2000.
Long nucleotide insertions between the HN and L protein coding regions of human parainfluenza virus type 3 yield viruses with temperature-sensitive and attenuation phenotypes.
Virology
272:225-234[CrossRef][Medline].
|
| 42.
|
Skiadopoulos, M. H.,
S. R. Surman,
M. St. Claire,
W. R. Elkins,
P. L. Collins, and B. R. Murphy.
1999.
Attenuation of the recombinant human parainfluenza virus type 3 cp45 candidate vaccine virus is augmented by importation of the respiratory syncytial virus cpts530 L polymerase mutation.
Virology
260:125-135[CrossRef][Medline].
|
| 43.
|
Stittelaar, K. J.,
L. S. Wyatt,
R. L. de Swart,
H. W. Vos,
J. Groen,
G. van Amerongen,
R. S. van Binnendijk,
S. Rozenblatt,
B. Moss, and A. D. Osterhaus.
2000.
Protective immunity in macaques vaccinated with a modified vaccinia virus Ankara-based measles virus vaccine in the presence of passively acquired antibodies.
J. Virol.
74:4236-4243[Abstract/Free Full Text].
|
| 44.
|
Taylor, J.,
R. Weinberg,
J. Tartaglia,
C. Richardson,
G. Alkhatib,
D. Briedis,
M. Appel,
E. Norton, and E. Paoletti.
1992.
Nonreplicating viral vectors as potential vaccines: recombinant canarypox virus expressing measles virus fusion (F) and hemagglutinin (HA) glycoproteins.
Virology
187:321-328[CrossRef][Medline].
|
| 45.
|
Taylor, W. R.,
R. K. Mambu,
M. ma-Disu, and J. M. Weinman.
1988.
Measles control efforts in urban Africa complicated by high incidence of measles in the first year of life.
Am. J. Epidemiol.
127:788-794[Abstract/Free Full Text].
|
| 46.
|
Valsamakis, A.,
P. G. Auwaerter,
B. K. Rima,
H. Kaneshima, and D. E. Griffin.
1999.
Altered virulence of vaccine strains of measles virus after prolonged replication in human tissue.
J. Virol.
73:8791-8797[Abstract/Free Full Text].
|
| 47.
|
van Wyke Coelingh, K. L.,
B. R. Murphy,
P. L. Collins,
A. M. Lebacq-Verheyden, and J. F. Battey.
1987.
Expression of biologically active and antigenically authentic parainfluenza type 3 virus hemagglutinin-neuraminidase glycoprotein by a recombinant baculovirus.
Virology
160:465-472[CrossRef][Medline].
|
| 48.
|
van Wyke Coelingh, K. L.,
C. Winter, and B. R. Murphy.
1985.
Antigenic variation in the hemagglutinin-neuraminidase protein of human parainfluenza type 3 virus.
Virology
143:569-582[CrossRef][Medline].
|
| 49.
|
Wild, F.,
P. Giraudon,
D. Spehner,
R. Drillien, and J. P. Lecocq.
1990.
Fowlpox virus recombinant encoding the measles virus fusion protein: protection of mice against fatal measles encephalitis.
Vaccine
8:441-442[CrossRef][Medline].
|
| 50.
|
Wild, T. F.,
A. Bernard,
D. Spehner, and R. Drillien.
1992.
Construction of vaccinia virus recombinants expressing several measles virus proteins and analysis of their efficacy in vaccination of mice.
J. Gen. Virol.
73:359-367[Abstract/Free Full Text].
|
| 51.
|
World Health Organization.
1994.
Expanded programme on immunization. Accelerated measles strategies.
Wkly. Epidemiol. Rec.
69:229-234[Medline].
|
| 52.
|
Wright, P. F.,
R. A. Karron,
R. B. Belshe,
J. Thompson,
J. E. Crowe, Jr.,
T. G. Boyce,
L. L. Halburnt,
G. W. Reed,
S. S. Whitehead,
E. L. Anderson,
A. E. Wittek,
R. Casey,
M. Eichelberger,
B. Thumar,
V. B. Randolph,
S. A. Udem,
R. M. Chanock, and B. R. Murphy.
2000.
Evaluation of a live, cold passaged, temperature-sensitive, respiratory syncytial virus vaccine candidate in infancy.
J. Infect. Dis.
182:1331-1342[CrossRef][Medline].
|
| 53.
|
Wyatt, L. S.,
S. T. Shors,
B. R. Murphy, and B. Moss.
1996.
Development of a replication-deficient recombinant vaccinia virus vaccine effective against parainfluenza virus 3 infection in an animal model.
Vaccine
14:1451-1458[CrossRef][Medline].
|
| 54.
|
Zhu, Y.,
P. Rota,
L. Wyatt,
A. Tamin,
S. Rozenblatt,
N. Lerche,
B. Moss,
W. Bellini, and M. McChesney.
2000.
Evaluation of recombinant vaccinia virusmeasles vaccines in infant rhesus macaques with preexisting measles antibody.
Virology
276:202-213[CrossRef][Medline].
|
| 55.
|
Zhu, Y. D.,
G. Fennelly,
C. Miller,
R. Tarara,
I. Saxe,
B. Bloom, and M. McChesney.
1997.
Recombinant bacille Calmette-Guerin expressing the measles virus nucleoprotein protects infant rhesus macaques from measles virus pneumonia.
J. Infect. Dis.
176:1445-1453[Medline].
|
Journal of Virology, November 2001, p. 10498-10504, Vol. 75, No. 21
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10498-10504.2001
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