The effect of preexistent virus-neutralizing antibodies on the active induction of antiviral T cell
responses was studied in two model infections in mice. Against the noncytopathic lymphocytic choriomeningitis virus (LCMV), pretreatment with neutralizing antibodies conferred immediate protection against systemic virus spread and controlled the virus below detectable levels.
However, presence of protective antibody serum titers did not impair induction of antiviral cytotoxic T lymphocyte (CTL) responses after infection with 102 PFU of LCMV. These CTLs
efficiently protected mice independent of antibodies against challenge with LCMV-glycoprotein recombinant vaccinia virus; they also protected against otherwise lethal lymphocytic choriomeningitis caused by intracerebral challenge with LCMV-WE, whereas transfused antibodies
alone did not protect, and in some cases even enhanced, lethal lymphocytic choriomeningitis.
Against the cytopathic vesicular stomatitis virus (VSV), specific CTLs and Th cells were induced in the presence of high titers of VSV-neutralizing antibodies after infection with 106
PFU of VSV, but not at lower virus doses. Taken together, preexistent protective antibody titers controlled infection but did not impair induction of protective T cell immunity. This is
particularly relevant for noncytopathic virus infections since both virus-neutralizing antibodies
and CTLs are essential for continuous virus control. Therefore, to vaccinate against such viruses parallel or sequential passive and active immunization may be a suitable vaccination strategy to combine advantages of both virus-neutralizing antibodies and CTLs.
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Introduction |
Effective control of acute pathogens is usually mediated
by the combination of humoral and cellular immune
responses. Vaccines used presently against human pathogens
primarily induce protective humoral immune responses.
However, an isolated humoral immune response is not sufficient for control, particularly against persistent infections
with non- or low cytopathic viruses (1). Subprotective levels of neutralizing antibodies may even risk an antibody-dependent enhancement of disease (4, 5), which may be
caused by antibodies influencing the balance between virus
spread and CTL response-mediating immunopathology.
Here we studied whether neutralizing antibodies influenced induction of a CTL response in the well-studied
model infections of mice with the noncytopathic lymphocytic choriomeningitis virus (LCMV) and the cytopathic
vesicular stomatitis virus (VSV). The results indicate that
active vaccination of hosts exhibiting preexistent neutralizing antibodies permits efficient induction of protective T
cell immune responses without dangerous enhancement of
immunopathology. Therefore, infection accompanied by
passive antibody transfer may be a valid approach particularly for vaccination against noncytopathic viruses with a
tendency to persist, which are controlled by combined antibody and T cell responses.
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Materials and Methods |
Viruses.
The LCMV isolate WE (LCMV-WE) was obtained
from F. Lehmann-Grube (FASEB, Hamburg, Germany). The VSV
serotype Indiana (VSV-IND, Mudd-Sommer isolate) was obtained from B. Kolakowsky (FASEB, Geneva, Switzerland). The
following recombinant vaccinia viruses were used: Vacc-G2, expressing the full-length LCMV-glycoprotein precursor molecule
(gift from D.H.L. Bishop, Oxford University, Oxford, UK; reference 6); Vacc-IND-GP, expressing the glycoprotein of VSV-IND;
and Vacc-IND-NP, expressing the nucleoprotein of VSV-IND (both gifts from B. Moss, FASEB, Bethesda, MD; reference 7).
Mice.
Inbred C57BL/6 and BALB/c mice were purchased
from the Institut für Versuchstierkunde, University of Zürich.
CD8-deficient mice were provided by Tak W. Mak, FASEB,
Toronto, Canada (8).
Generation and Characterization of LCMV-neutralizing mAbs.
The LCMV-neutralizing mAb KL25 has been previously described (9, 10). The LCMV-neutralizing mAbs WEN3 and
WEN4 were generated as follows: CD8-deficient (H-2b) mice
and CD8-depleted (11) BALB/c (H-2d) mice were immunized
intravenously with 106 PFU LCMV-WE. After 40-60 d, mice
were boosted with 5 µg purified LCMV or with two intravenous
injections of 106 PFU LCMV-WE. 4 d later, spleen cells were
fused with P3x63Ag.8 mouse plasmacytoma cells. mAb WEN3
originated from a CD8-deficient mouse, and WEN4 from an
anti-CD8-treated BALB/c mouse. mAbs were purified by affinity chromatography (Protein G, Sepharose fast flow; Pharmacia
Biotech AB, Uppsala, Sweden). Antibody concentration was
measured by optical densitometry. The mAb VI22 neutralizes VSV-IND and has been previously described (12).
LCMV and VSV Titer and Neutralization Assay.
LCMV titers
from tissue homogenates and vaccinia titers from ovaries were determined as previously described (13, 14). Anti-LCMV- and
anti-VSV-neutralizing antibody titers were determined by in
vitro reduction of infectious foci or plaques, respectively, as previously described (13, 15).
Cytotoxicity Assay.
Spleen cells were restimulated in vitro for
5 d on either thioglycollate-induced (1 ml intraperitoneally 6 d
before day 1 of restimulation), LCMV-infected (200 PFU intraperitoneally 4 d before day 1 of restimulation) peritoneal macrophages or on spleen cells loaded with the VSV-NP peptide p49-
62 (16). Cytotoxic activity was assessed against peptide-loaded
MC57G target cells (LCMV-GP33-41, reference 17; LCMV-NP396-408, reference 18; VSV-NP49-62) in a standard 51Cr-release
assay (19). Spontaneous release was always <20%.
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Results and Discussion |
Neutralization of LCMV In Vivo.
Two newly selected
LCMV-neutralizing mAbs, WEN3 and WEN4, were compared to the LCMV-neutralizing mAb KL25 (9) with respect to their neutralizing capacity in C57BL/6 mice. Intraperitoneal transfer of 200 µg of purified mAb led to
LCMV-neutralizing serum antibody titers of 1/80 to 1/40
on days 1, 2, and 4 after mAb treatment. Mice were intravenously infected with 200 PFU of LCMV-WE 4 h after
antibody treatment. On day 4 after infection, when the virus reaches maximal titers in naive mice, LCMV titers were
determined in spleen. All mAb-treated mice had LCMV-WE titers below detection limits (Fig. 1 A). Mice treated
intraperitoneally with different doses of purified mAb WEN3
and intravenously infected with 200 PFU of LCMV-WE 4 h
later were optimally protected after transfer of 200 µg of
the mAb (Fig. 1 B). Similar results were obtained after
transfer of mAbs KL25 and WEN4 (data not shown). To
exclude the possibility that LCMV in spleen was only
masked by neutralizing mAbs the following experiment
was performed: mice were treated with 200 µg of the mAb
KL25 4 h before intravenous infection with 200 PFU of
LCMV-WE; 5 d later, one group of mice was perfused with PBS under general anesthesia and then killed. Viral titers in spleen were determined. Irrespective of perfusion,
all mAb-treated mice showed reduction of replicating virus
below detection limit, whereas in untreated controls, high
titers of replicating virus were present. Furthermore, we
failed to detect neutralizing activity in organ homogenates
of mice given 200 µg of the neutralizing mAb KL25 5 d
before death (data not shown).

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Fig. 1.
In vivo neutralizing
capacity of mAb. (A) C57BL/6
mice were given 200 µg of mAb
intraperitoneally or left untreated
(open bars); 4 h later, mice were
infected intravenously with 200 PFU of LCMV-WE. On day 4, LCMV titers were determined in
spleen by an infectious focus formation assay. (B) Dose dependence of in vivo LCMV neutralization. Mice were given 200, 20, or 2 µg of mAb WEN3 intraperitoneally 4 h before infection with 200 PFU of LCMV-WE. Control mice were left untreated. Virus titer in spleen was determined on day
4 after infection. Similar results were obtained for mAb KL25 and
WEN4. Values represent means of three mice (+ SEM) per group of one
of three representative experiments. *, Reduction of LCMV titer below
detection limit.
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Virus-specific CTLs Are Induced in the Presence of Protective
Levels of Neutralizing mAb.
Transfused LCMV-neutralizing
mAbs have been demonstrated to protect against LCMV after
systemic intravenous infection (4, 20). To test whether under
such conditions induction of antiviral protective memory
CTLs is still possible, CTL induction was analyzed after infection with LCMV-WE in the presence of neutralizing
mAb; mice were treated intraperitoneally with 200 µg of
mAb KL25 and infected intravenously with 200 PFU of
LCMV-WE 4 h later. On day 20 after infection, lytic activity of spleen cells was tested in a 51Cr-release assay after 5 d
restimulation in vitro, (Fig. 2, A-C). LCMV-specific CTL
activities were only marginally reduced in mAb-treated mice when compared to untreated mice. Similar results were
obtained after treatment with mAbs WEN3 and WEN4
(data not shown).

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Fig. 2.
Lytic activity of spleen cells from mAb-treated mice.
C57BL/6 mice were transferred with 200 µg of the LCMV-neutralizing
mAb KL25 ( , A-C), the VSV-neutralizing mAb VI22 ( , D-I), or left untreated ( , A-I) and were intravenously infected with 200 PFU of
LCMV-WE (A-C), 2 × 106 PFU (D and E), 104 PFU (F and G), or 103
PFU (H and I) VSV-IND, respectively. At day 20 after infection, spleen
cells were restimulated in vitro for 5 d, and CTL activity was determined
in a standard 5-h 51Cr-release assay on MC57G target cells loaded with
the LCMV-derived peptides GP33 (A) and NP396 (B), the VSV derived
peptide NP49 (D, F, and H), or on unloaded target cells (C, E, G, I).
Shown are values of individual mice from one of three similar experiments. Spontaneous release was <20%.
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These findings were confirmed for infections of mice with
VSV. Mice were intraperitoneally treated with 100 µg of the
VSV-neutralizing mAb VI22 4 h prior to intravenous infection with 2 × 106 PFU VSV-IND. This transfer of mAb
led to VSV-neutralizing serum titers of 1/20000, which has
been shown to protect against lethal VSV infection (21).
Similar to the LCMV infection experiments, mice treated
with VSV-neutralizing mAb VI22 exhibited VSV-specific memory CTL activity comparable to untreated control
mice (Fig. 2, D and E). Importantly, CTL induction in the
presence of VSV-neutralizing mAbs was dose-dependent;
although doses of 104 and 103 PFU of the abortively replicating VSV-IND intravenously induced VSV-specific memory CTL, the same low doses given after treatment with
mAb VI22 did not (Fig. 2, F -I).
CTL Induced in the Presence of Neutralizing mAbs Protect
Against Virus Challenge.
To test whether the CTL induced in the presence of neutralizing mAbs exhibited antiviral protective capacity independent of neutralizing mAb,
mice were challenged with recombinant vaccinia viruses expressing LCMV-GP (Vacc-G2), VSV-GP (Vacc-IND-GP),
or VSV-NP (Vacc-IND-NP), respectively (6, 7). These vaccinia viruses do not express the recombinant proteins on
the virus surface (22, 23). Therefore, protection against vaccinia recombinants cannot be mediated by antibodies, but
is due to preactivated T cells (14, 22). In C57BL/6 mice,
the protection against Vacc-G2 has been shown to be mediated by LCMV-specific CTLs (14). Female C57BL/6 mice
were intraperitoneally treated with 200 µg of mAb KL25
or WEN3 (passive vaccination) and intravenously infected with 200 PFU of LCMV-WE 4 h later (active vaccination).
10 d after LCMV priming, mice were intraperitoneally
challenged with 4 × 106 PFU of Vacc-G2 (challenge infection), and vaccinia titers in ovaries were determined 5 d later
(Table 1). Mice treated with LCMV-neutralizing mAb and
primed with LCMV-WE were equally protected against
Vacc-G2 compared with control mice, which were only
primed with LCMV-WE. LCMV-neutralizing mAb alone
had no anti-Vacc-G2 protective effect.
Similar data were obtained with VSV. In C57BL/6 mice,
protection against Vacc-IND-NP is mediated by VSV-specific CD8+ T cells, whereas protection against Vacc-IND-GP is mediated by VSV-specific CD4+ T cells (14). Female
C57BL/6 mice were intraperitoneally treated with 100 µg
of the VSV-neutralizing mAb VI22 (passive vaccination) and intravenously infected with 2 × 106 PFU VSV-IND 4 h
later (active vaccination). 10 d after VSV-priming, mice were
challenged intraperitoneally with 4 × 106 PFU of Vacc-IND-NP or Vacc-IND-GP, respectively (challenge infection). As summarized in Table 2, CTL-mediated protection against Vacc-IND-NP was comparable in mAb treated
plus VSV-primed mice and in VSV-primed only control
mice. After Vacc-IND-GP infection, which in H-2b mice
is controlled by CD4+ T cells, viral titers were reduced
from 5.9 log PFU to 3.1 log PFU per ovary in mAb-treated plus VSV-primed mice and were below detection
limits of 1.7 log PFU per ovary in VSV-primed only control mice. Apparently, CD4+ T cells are less efficiently
primed in the presence of limiting antigen doses.
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Table 2
Effect of protective VSV Neutralizing Antibody on
Induction of Protective Cytotoxic T Cells and Helper T Cells
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To further investigate the protective capacity of CTLs
induced in the presence of neutralizing mAb serum titers,
prevention of LCMV-induced lethal choriomeningitis by
preactivated CTLs was tested. Lethal choriomeningitis is
caused by LCMV-specific CTL-mediated immunopathology after intracerebral infection with low dose of LCMV-WE (24). Earlier studies had shown that transfused LCMV-neutralizing hyperimmune sera did not protect against fatal
choriomeningitis after intracerebral infection with a low
dose of LCMV-WE (4). Choriomeningitis is prevented if
CTLs are preactivated before intracerebral infection (25). If
CTLs can be primed efficiently in the presence of LCMV-neutralizing mAb, mice should be protected against lethal
choriomeningitis caused by a subsequent intracerebral infection with LCMV-WE. To test this, mice were treated intraperitoneally with 200 µg of LCMV-neutralizing mAb
KL25 or WEN3 and intravenously primed with 200 PFU
of LCMV-WE 20 d before intracerebral challenge. Control
mice either were treated with only mAb 4 h before intracerebral challenge, or primed intravenously with LCMV-WE
20 d before intracerebral challenge, or left completely untreated. Mice were challenged intracerebrally with 30-300
PFU of LCMV-WE. All mice intravenously primed with
LCMV-WE survived intracerebral challenge infection irrespective of the presence or absence of LCMV-neutralizing mAb during priming (Fig. 3 A). Neutralizing mAb
alone did not prevent lethal choriomeningitis induced by
LCMV-WE (Fig. 3 B).

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Fig. 3.
No CTL-mediated choriomeningitis was detectable in mice
pretreated with mAb and infected with LCMV-WE. 20 d before intracerebral challenge, groups of six C57BL/6 mice were treated with 200 µg of mAb KL25 ( ), WEN3 ( ), and were intravenously primed with 200 PFU of LCMV-WE 4 h after treatment or were intravenously primed with 200 PFU LCMV-WE only ( ). Control mice were treated with 200 µg of mAbs KL25 ( ) or WEN3 ( ) 4 h before intracerebral challenge, or left completely untreated ( ) before intracerebral challenge. All
mice were challenged intracerebrally with 30-300 PFU of LCMV-WE, and survival was monitored twice daily.
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The fact that mice infected with a low dose (102 PFU) of
LCMV induced a protective CTL response in the presence
of high levels of neutralizing antibodies is surprising, and
may suggest that a CTL response against this noncytopathic
virus can be induced with very little to undetectable levels
of viral antigen. In contrast, in the presence of VSV-neutralizing antibody titers, CTL specific for the cytopathic
VSV were only induced after a high dose (106 PFU) virus
infection. Similarly, protective VSV-specific Th cells were
induced only to a reduced level in the presence of high titers of neutralizing antibodies. This confirms previous reports showing inhibitory effects of maternally transferred or
passively transfused immune sera against cytopathic viruses
such as respiratory syncytial virus, rabies virus, and influenza virus, where preexistent neutralizing antibodies impaired induction of CTLs (26). Like VSV, and in contrast to LCMV, infections with these viruses are efficiently controlled by primary antibody responses. Preexistent antibody titers seem to very effectively neutralize virus, so that
no or insufficient antigen is generated; thereby induction of
CTLs is impaired in a dose-dependent manner.
Combinations of active and passive immunization are used
in adults for antivaccinia virus vaccination, where immune
sera are administered in parallel to active immunization if
complications are expected. Similar strategies have been
discussed for vaccinations against hepatitis virus A and B or
for herpes simplex viruses. This study indicates that vaccination strategies that combine passive and active immunization are effective and may be especially advantageous for
achieving protective immunity against viruses that tend to
establish persistent infections and that are only well controlled by combined action of antibodies and CTLs (possibly including HIV; references 3, 30, 31).
Received for publication Received for publication 4 October 1997 and in revised form 1 December 1997..
This work was supported by Swiss National Science Foundation grants 31-32195.91, 31-32179.91, 31-50884.97, and 31-50900.97.
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