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Journal of Virology, May 2000, p. 4652-4657, Vol. 74, No. 10
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Successful Vaccine-Induced Seroconversion by
Single-Dose Immunization in the Presence of Measles Virus-Specific
Maternal Antibodies
Bernd
Schlereth,1
John K.
Rose,2
Linda
Buonocore,2
Volker
ter Meulen,1 and
Stefan
Niewiesk1,*
Institute of Virology and Immunobiology,
University of Wuerzburg, 97078 Wurzburg,
Germany,1 and Departments of
Pathology and Cell Biology, Yale University School of Medicine, New
Haven, Connecticut 065102
Received 13 December 1999/Accepted 14 February 2000
 |
ABSTRACT |
In humans, maternal antibodies inhibit successful immunization
against measles, because they interfere with vaccine-induced seroconversion. We have investigated this problem using the cotton rat
model (Sigmodon hispidus). As in humans, passively
transferred antibodies inhibit the induction of measles virus
(MV)-neutralizing antibodies and protection after immunization with MV.
In contrast, a recombinant vesicular stomatitis virus (VSV) expressing
the MV hemagglutinin (VSV-H) induces high titers of neutralizing
antibodies to MV in the presence of MV-specific antibodies. The
induction of neutralizing antibodies increased with increasing virus
dose, and all doses gave good protection from subsequent challenge with MV. Induction of antibodies by VSV-H was observed in the presence of
passively transferred human or cotton rat antibodies, which were used
as the models of maternal antibodies. Because MV hemagglutinin is not a
functional part of the VSV-H envelope, MV-specific antibodies only
slightly inhibit VSV-H replication in vitro. This dissociation of
function and antigenicity is probably key to the induction of a
neutralizing antibody in the presence of a maternal antibody.
| |
INTRODUCTION |
Measles virus (MV) is the single
most important cause of infant mortality worldwide. Vaccination with an
attenuated live virus vaccine has proven to induce protective immunity
in seronegative individuals, and even low titers of neutralizing
antibodies seem to be protective (4, 12). In developing
countries with a high level of infection, infants below the age of 12 months are at high risk for MV infection. In this age group passively
transferred maternal immunoglobulins (Ig) pose a problem because
declining maternal antibodies interfere with vaccine-induced
seroconversion but do not protect against infection with wild-type MV
(13, 15). To induce immunity in the presence of maternal
antibodies, high-titer vaccines (>104.7 PFU) were
administered to infants at the age of 4 to 6 months (1, 17).
These infants showed good serological responses and protection against
measles. However, especially in female children, an increased mortality
due to infections other than measles was observed after immunization
with high-titer vaccines (2, 7), and the use of this vaccine
was therefore discontinued.
In order to develop vaccine alternatives which induce MV-neutralizing
antibodies in the presence of maternal antibodies, we have used MV
infection in the cotton rat model (Sigmodon hispidus, inbred
strain Cotton NIco) (9). Cotton rats are the only rodents in
which MV replicates in the respiratory tract (18). Here we demonstrate that the passive transfer of human serum containing MV-specific antibodies inhibits vaccine-induced seroconversion and
abolishes protection against MV. To induce neutralizing antibodies in
the presence of MV-specific antibodies, we tested a recombinant vesicular stomatitis virus (VSV) expressing the MV hemagglutinin (VSV-H) (14). VSV is known for the rapid induction of
neutralizing antibodies against its surface protein G, and VSV
recombinants expressing influenza virus hemagglutinin induce high
neutralizing antibody titers to influenza virus in mice (10,
11). In the recombinant VSV-H, the MV hemagglutinin is
incorporated into the bullet-shaped envelope and comprises about
one-fourth of the envelope proteins in the envelope but is not needed
for replication. Using this vector we show here that intranasal (i.n.)
but not intraperitoneal (i.p.) immunization led to the induction of
MV-neutralizing antibodies in the presence of maternal antibodies.
| |
MATERIALS AND METHODS |
Cotton rats: infection, immunization, serum transfer, and virus
titration.
Cotton rats (inbred strain Cotton/NIco) were obtained
from Iffa Credo, Lyon, France. Animals were kept under controlled
environmental conditions and used at the age of 6 to 8 weeks (60 to
70 g). The i.n. infection, i.p. infection or serum injection, and
retro-orbital blood sampling were done under ether narcosis. To mimic
maternal MV-specific antibodies, 1 ml of a human serum (antibody
concentration of 16 IU/ml by enzyme-linked immunosorbent assay
[ELISA]; antibody titer of 320 by neutralization (NT) assay and 256 by hemagglutination inhibition assay) was used. For challenge
experiments, 4 days after i.n. infection with 5 × 105
PFU of MV HU2 strain in a volume of 50 to 100 µl, animals were asphyxiated using CO2, lungs were removed, and the 50%
tissue culture infectious dose (TCID50) was determined as
described previously (9).
Viruses.
Recombinant VSV and VSV-H (14) were
grown and titrated on baby hamster kidney (BHK) cells, and MV strains
Edmonston B and HU2 were grown and titrated on Vero cells according to
standard procedures (9, 14).
ELISA.
ELISAs were performed according to standard
procedures. For ELISA 10 µg of gradient-purified, UV-inactivated
MV/ml was coated in 200 mM NaCO3 buffer (pH 9.6) at 4°C
overnight, blocked with phosphate-buffered saline-10% fetal calf
serum-0.05% Tween 20, and incubated with dilutions of human serum at
room temperature for 1 h. After being washed, the plate was
incubated for 1 h at room temperature with a horseradish
peroxidase-coupled rabbit serum specific for human IgG (Dako, Hamburg,
Germany) and was subsequently developed with 0.5 mg of
ortho-phenyldiamine/ml in buffer (35 mM citrate, 66 mM
Na2HPO4 [pH 5,2])-0.01%
H2O2. Human sera were standardized using human
anti-MV serum (2nd international standard 1990; 5 IU per ml; National
Institute for Biological Standards and Control, Potters Bar, United Kingdom).
To test for MV-specific cotton rat IgG, coated plates were incubated
with dilutions of cotton rat serum at 4°C for 1 h. After being
washed, the plate was incubated with rabbit serum specific for cotton
rat IgG (Virion Systems, Rockville, Md.) for 1 h at room
temperature. After being washed, the plate was incubated with
horseradish peroxidase-coupled goat serum specific for rabbit IgG
(Zymed, San Francisco, Calif.) for 45 min at room temperature and
developed as described above.
NT and PRNT assays. (i) NT assay.
Serum dilutions were
incubated with 50 PFU of MV Edmonston strain or recombinant VSV or
VSV-H for 1 h at 37°C and plated in duplicate onto
104 Vero cells (MV) or BHK cells (VSV) per well of a
96-well plate. Two (VSV) or 5 days (MV) later titers were determined microscopically.
(ii) Plaque reduction neutralization (PRNT) assay.
Serum
dilutions were incubated with 100 PFU of MV Edmonston strain for 1 h at 37°C and plated onto Vero cells (80 to 90% density) in a
six-well plate. Cells were overlayed with agar, and after 5 days the
incubation mixture was stained with neutral red (Merck) solution (0.6%
in phosphate-buffered saline) and the plaques were counted.
| |
RESULTS |
Both cotton rat and human MV-specific antibodies inhibit
vaccine-induced seroconversion in cotton rats.
Weanling cotton
rats from MV-immune dams have high serum titers of both MV-neutralizing
antibodies (NT assay titer, 180 ± 60) and total MV-specific
antibodies (optical density, 2.1 ± 0.04) at 3 weeks after birth.
As in humans, antibody titers decline over time, and no neutralizing
antibodies were detectable after 8 weeks. At 3 weeks after birth,
animals with high titers of maternal antibodies were immunized i.p.
with the MV Edmonston vaccine strain. Seven weeks later no neutralizing
antibodies were detectable (data not shown). In contrast, vaccinated
animals lacking maternal antibodies developed antibody titers that were
detectable for at least 10 months. Although the protection by maternal
antibodies is similar to the situation in humans, it is difficult in
our model system to distinguish between actively induced antibodies and
passively transferred maternal antibodies. Because human and cotton rat antibodies can be distinguished by ELISA, we chose in all initial experiments to use an MV-specific human serum (containing 16 IU/ml as
defined by comparison to a World Health Organization standard serum) to
mimic maternal antibodies. After transfer of 1 ml (16 IU of antibodies)
of human serum into cotton rats, MV-specific antibodies declined over 6 weeks (Fig. 1a). By using the sensitive PRNT assay, neutralizing antibodies were detected for 3 weeks after
serum transfer (Fig. 1b). Some of the animals given the neutralizing
antibody were also challenged with MV at the time points indicated
(Fig. 1c). The presence of antibodies correlated with
greater-than-10-fold reductions in viral titers in lungs of infected
animals for the first 3 weeks. With declining antibody titers,
protection from MV infection declined also and was gone by week 7. As
in humans, the NT assay was relatively insensitive compared to the PRNT
assay and ELISA and significant reduction in virus replication was
still seen when antibody titers were below the threshold of detection.
We also measured the inhibition of measles vaccine-induced
seroconversion by MV-specific antibodies. One day after serum transfer
animals were immunized with 105 PFU of MV i.p., which
induced high titers of MV-specific and neutralizing antibodies (Fig.
2).. In the presence of transferred human
MV-specific antibodies, however, the generation of total MV-specific
antibody titers was reduced more than fourfold and neutralizing
antibody titers were abrogated (Fig. 2). In consequence, subsequent
protection in these animals was severely reduced compared to that in
animals immunized in the absence of MV-specific antibodies (Fig. 2).
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FIG. 1.
MV-specific human antibodies mimic maternal antibodies
and decline after transfer into cotton rats. One milliliter of human
serum containing MV-specific antibodies (16 IU/ml) was transferred into
naive cotton rats (60 to 70 g). One day later and at weekly
intervals from weeks 1 to 7, human MV-specific antibody titers (six
animals per time point) were measured by ELISA (a) and virus NT and
PRNT assays (b). At the same time points animals were challenged i.n.
with MV, and virus titers (TCID50/g of lung tissue ± standard deviation) were determined by titration 4 days later (four
animals per time point, except week 1 [one animal]) (c). By NT assay
neutralizing antibodies can be demonstrated until week 2, by the
more-sensitive PRNT assay they can be demonstrated until week 3, and by
ELISA they can be demonstrated until week 6 (26 mIU/ml). In the
presence of neutralizing antibodies the virus reduction is more than
10-fold and declines from week 4.
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FIG. 2.
MV-specific human antibodies inhibit vaccine-induced
seroconversion and protection in cotton rats. One milliliter of human
serum containing MV-specific antibodies (16 IU/ml) was transferred into
naive cotton rats. One day later animals were immunized i.p. with
105 PFU of MV and challenged after 6 weeks with MV i.n. The
total MV-specific antibodies were measured by ELISA (1:100 dilution),
and the neutralizing antibodies were measured by NT assay. Virus titers
in lung tissue (± standard deviations) were determined on day 5 after
i.n. infection. Data represent the averages for five animals. The
difference in protection was significant between groups with and
without serum transfer (P < 0.0003; two-sided paired
t test). OD, optical density.
|
|
The i.n. immunization with VSV-H results in more-rapid generation
of neutralizing antibodies and higher titers than does immunization
with MV.
Recombinant VSV-H (14) was chosen to be tested
for the induction of MV-neutralizing antibodies for the following
reasons: the MV hemagglutinin is the most important antigen for the
induction of neutralizing antibodies (6), VSV is known for
rapid and efficient induction of neutralizing antibody responses
directed against its own surface G protein (3), and MV
hemagglutinin comprises 25% of the total envelope protein in the
recombinant VSV-H (14). First, the ability of VSV-H to
induce neutralizing antibodies in comparison to MV was tested after
i.p. and i.n. immunization. In comparison with the MV Edmonston strain,
VSV-H induced higher titers of neutralizing and total MV-specific
antibodies (Fig. 3). The difference was
especially striking after i.n. immunization, indicating that VSV-H is a
vector well suited for i.n. immunization.
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FIG. 3.
VSV-H induces higher titers of neutralizing antibodies
than MV. After inoculation of 5 × 106 PFU of VSV-H or
MV i.p. or i.n., MV-specific antibodies were measured by NT assay (a)
and by ELISA (1:100 dilution; b) in weekly intervals from week 1 to 4 after immunization. All data represent the means for five animals ± standard deviations. Four weeks after i.n. immunization with MV, the
neutralizing antibody titer, 15, was above the threshold level of
detection (>10). The percentage of MV-specific IgA antibodies in whole
serum remained constant irrespective of the virus or route of
immunization used. OD, optical density.
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|
MV-specific antibodies do not inhibit VSV-H replication in
vitro.
To induce MV-neutralizing antibodies in vivo, in the
presence of MV-specific antibodies, VSV-H would have to escape
neutralization by MV-specific antibodies. Although MV hemagglutinin is
expressed in considerable quantities as part of the envelope of VSV-H,
it is a passenger protein with no function in viral replication. We
assumed that replication of VSV-H might therefore not be inhibited by
MV-specific antibodies to the same degree as MV replication. In vitro,
serum containing antibodies against glycoprotein G of VSV effectively
neutralized VSV-H (data not shown). Human and cotton rat sera
containing high titers of MV-neutralizing antibodies (1:640)
neutralized MV effectively, but only very high serum concentrations neutralized VSV-H (1:20). Thus VSV-H effectively escapes neutralization by antibody concentrations that completely neutralize MV in vitro.
VSV-H induces MV-neutralizing antibodies in the presence of
MV-specific antibodies.
To test whether VSV-H is able to replicate
in the presence of MV-specific antibodies in vivo, cotton rats were
immunized with VSV-H either i.p. or i.n. or with MV i.n. 1 day after
serum transfer. After i.p. immunization with VSV-H or i.n. immunization
with MV, antibody production was severely suppressed as measured by NT assay and ELISA (Fig. 4) compared to
immunization in the absence of MV-specific antibodies (Fig. 3). In
contrast, after i.n. immunization with VSV-H, total MV-specific as well
as neutralizing antibody production started after 4 weeks. This effect
was dose dependent. An inoculum of 5 × 105 PFU of
VSV-H overcame MV-specific antibodies (NT assay titer, 17.5), but a
40-fold increase in the virus inoculum gave approximately 3-fold-increased titers of neutralizing antibodies (Table
1). Viral replication was shown to be
critical for antibody induction, as UV-inactivated VSV-H was not able
to induce neutralizing antibodies (data not shown). Although the titers
of neutralizing antibodies in animals without serum transfer were
higher, no difference in protection between animals with and without
serum transfer was seen (Table 1).
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FIG. 4.
Immunization via the i.n. route with VSV-H overcomes
maternal antibodies. After transfer of 16 IU of MV-specific human
antibodies into cotton rats, animals were immunized 1 day later with
2 × 107 PFU of MV i.n. (three animals) or 2 × 107 PFU of VSV-H i.n. (four animals per group) or 5 × 107 PFU of VSV-H i.p. (four animals per group). On the day
of immunization (day 1) and after 1, 2, 3, 4, and 6 weeks serum samples
were obtained and tested for the presence of neutralizing antibodies by
NT assay (top) and of MV-specific cotton rat antibodies by ELISA
(bottom). After 3 weeks neutralizing antibodies fell below the level of
detection indicating that neutralizing antibodies from week 4 onwards
were produced by cotton rats. This is confirmed by the ELISA data. OD,
optical density.
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TABLE 1.
Induction of MV-neutralizing antibodies and protection
against MV-infection by VSV-H in the presence of MV-specific
antibodiesa
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|
Interestingly, serum transfer of MV-specific antibodies inhibited the
generation of hemagglutinin-specific antibodies, as
the titers of
VSV-neutralizing antibodies were the same in both
groups.
Immunization with VSV-H also overcomes maternal (MV-specific)
cotton rat antibodies.
We performed an experiment to determine if
VSV-H was able to overcome homologous cotton rat anti-MV antibodies in
addition to human MV-specific antibodies. Cotton rats from MV-immune
dams with high titers of maternally derived MV-specific antibodies were
given VSV-H i.n. As shown in Fig. 5 an
increase in anti-MV antibodies was detectable by NT assay and by ELISA
in the vaccinated animals after 3 to 7 weeks, while the maternal
antibodies declined in the control animals.
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FIG. 5.
Induction of neutralizing antibodies by VSV-H in the
presence of maternal (cotton rat) antibodies. Five-week-old cotton rats
from MV-immune dams were immunized with 5 × 106 PFU
of VSV-H (four animals) or left untreated (three animals) (day 0). At
various time points MV-specific antibody titers were tested by NT assay
(top) and ELISA (bottom). OD, optical density.
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| |
DISCUSSION |
Maternal antibodies are an early line of specific immune defense
to protect the newborn against bacterial and viral pathogens which have
been encountered by the mother. To immunize against measles in the
presence of maternal antibodies has proven to be difficult because
declining MV-specific maternal antibodies inhibit vaccine-induced
seroconversion but do not confer protection against wild-type MV
infection. In addition, maternal antibody titers differ between infants
from immunized versus naturally infected mothers. In the latter, titers
are higher and persist longer (8). Therefore it is desirable
to be able to use a measles vaccine irrespective of the titer of
maternal antibodies.
The cotton rat proved to be a suitable animal model to test vaccine
candidates. Similar to the situation in human populations, the
declining maternal MV-specific antibodies inhibit vaccine-induced seroconversion in cotton rats and protection against MV is severely reduced. In an experimental study with monkeys it was shown that a
prime boost strategy (two immunizations with a 4-week interval) overcomes maternal antibodies (16). After immunization with MV or immune system-stimulating complexes containing the MV
glycoproteins hemagglutinin and fusion protein, neutralizing antibodies
were induced and protection against MV challenge was observed. However, repeated vaccinations are difficult in countries with migrating populations or when mass vaccination campaigns are undertaken. In
humans, attempts have been made to immunize in the presence of maternal
antibodies by a single aerosol dose of vaccine (for a review see
reference 5) or by subcutaneous (s.c.) injection of
a high-titer vaccine (2, 7). Whereas vaccination by aerosol has not given results superior to s.c. application, high-titer vaccines
can achieve seroconversion in the presence of maternal antibodies and
protect against measles. However, probably because of the marked
immunosuppressive effect of this high-titer vaccine, a subsequent
higher mortality due to secondary infections was noted.
We have chosen the highly attenuated recombinant VSV-H to immunize
cotton rats against MV challenge (14). In cotton rats the
attenuated recombinant VSV-H induces, after i.p. and especially after
i.n. immunization, much higher titers of MV-neutralizing antibodies
than MV itself. This response could be due to rapid replication and
high-level MV hemagglutinin production in vivo by the VSV-H vector, but
other factors may be involved also. From studies with mice it is known
that VSV induces a T-cell-independent IgM response and high titers of
neutralizing antibodies specific for the VSV G protein (3).
This response may be due to the highly organized assembly of VSV G
protein in the rigid bullet-shaped envelope. In contrast, MV has a very
flexible pleomorphic envelope. The incorporation of MV hemagglutinin
into the VSV envelope might therefore render MV hemagglutinin more
antigenic. Immunization (i.n.) with VSV-H but not with MV induces
neutralizing antibodies in the presence of MV-specific antibodies.
VSV-H replicates for 5 days in lung tissue at lower titers than MV and
does not spread into peripheral organs (data not shown). Immunization
with UV-inactivated virus demonstrates that virus replication is
essential to induce neutralizing antibodies in the presence of
MV-specific antibodies. This is confirmed by the fact that after i.p.
inoculation VSV-H replicates abortively (data not shown). MV
hemagglutinin is part of the VSV-H envelope but has no function in
viral replication (14). The ability of VSV-H to escape
MV-specific antibodies in vitro is mirrored in the in vivo situation.
These data indicate that a replication-competent vector is required to
successfully immunize in the presence of maternal MV-specific
antibodies. The strategy of having the appropriate antigen encoded as a
passenger protein on the surface of a virus particle may be effective
in other cases where a strong antibody response must be generated in
the presence of maternal antibodies.
| |
ACKNOWLEDGMENTS |
This work was in part supported by Deutsche
Forschungsgemeinschaft, Bundesministerium für Bildung,
Wissenschaft, Forschung und Technologie, Pfleger-Stiftung, and by World
Health Organization and National Institutes of Health grants to J.K.R.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Institut
für Virologie und Immunbiologie, Versbacher Str. 7, 97078 Würzburg, Germany. Phone: 49 931 201 3441. Fax: 49 931 201 3934. E-mail: niewiesk{at}vim.uni-wuerzburg.de.
| |
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Journal of Virology, May 2000, p. 4652-4657, Vol. 74, No. 10
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
