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Infection and Immunity, November 1998, p. 5329-5336, Vol. 66, No. 11
Department of Tropical Medicine, University
of Hawaii, Honolulu, Hawaii 96816
Received 2 March 1998/Returned for modification 27 May
1998/Accepted 14 August 1998
Vaccine adjuvants exert critical and unique influences on the
quality of immune responses induced during active immunizations. We
investigated the mechanisms of action of immunological adjuvants in
terms of their requirements for cytokine-mediated pathways for
adjuvanticity. Antibody responses potentiated by several adjuvants to a Plasmodium falciparum MSP1-19 (C-terminal 19-kDa
processing fragment of MSP1) vaccine were studied in gamma interferon
(IFN- Effective induction of immune
responses to whole, subunit, or synthetic peptide vaccines often
requires coadministration of adjuvants or immunomodulators. Recent
research has led to the identification of a number of clinically
acceptable adjuvants which are more potent and efficacious than the
alum-type adjuvants (16, 17). Many of these compounds are
comparable to the "gold standard," i.e., complete Freund's
adjuvant (CFA), in inducing strong and/or protective
immunities against many infectious diseases in animal models (16,
17).
While the discoveries of potentially effective adjuvants for human
vaccines are encouraging, little is known regarding the mechanisms of
action of vaccine adjuvants in inducing a particular immune response
during in vivo, active immunizations. This is of particular concern
since vaccine adjuvants can have profound effects on the
qualities of immune responses induced. As examples, studies on animals
immunized with malaria vaccine antigens (i.e., sporozoite,
merozoite, and gametocyte antigens) show that adjuvants influence the specificities of immune responses induced, the major histocompatibility complex-regulated responsiveness to epitopes, and
the induction of protective immunity (4, 11, 13, 17, 18, 20, 28,
35, 41). Furthermore, the responses to adjuvants often vary with
animal species or subspecies (17). Such differential influences on immune responses occur despite the pleomorphic effects of
adjuvants on a variety of immune cells, and such effects often overlap
among different classes of adjuvants (16, 17, 22, 38, 39).
We hypothesize that during active immunizations, vaccine adjuvants
selectively or preferentially utilize different immune pathways for the
potentiation of an immune response. These may be in the form of
cytokine-potentiated pathways, selective costimulatory interactions, and/or preferential activation of
subpopulations of immune cells. To begin to address this
issue, we investigated the requirement of gamma interferon (IFN-
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Pathways for Potentiation of Immunogenicity during
Adjuvant-Assisted Immunizations with Plasmodium falciparum
Major Merozoite Surface Protein 1
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
) or interleukin (IL-4) knockout mice. The levels of
anti-MSP1-19 antibodies and the induction of Th1- and Th2-type
antibodies were analyzed. Results revealed a spectrum of
requirements for cytokine-mediated pathways in the potentiation
of immunogenicity, and such requirements were influenced by
interactions among individual components of the adjuvant formulations.
One adjuvant strictly depended on IFN- to induce appreciable
levels of anti-MSP1-19 antibodies, while some formulations required
IFN- only for the induction of Th1-type antibodies. Other
formulations induced exclusively Th2-type antibodies and were not
affected by IFN- knockout. There were three patterns of requirements
for IL-4 by various adjuvants in the induction of Th2-type anti-MSP1-19
antibodies. Moreover, the induction of Th1-type anti-MSP1-19 antibodies
by adjuvants showed two distinct patterns of regulation by IL-4. The
utilization of an IL-4 regulated pathway(s) for the induction of
Th2-type antibodies by the same adjuvant differed between mouse
strains, suggesting that animal species variability in responses to
vaccine adjuvants may be due, at least in part, to differences in the
utilization of immune system pathways by an adjuvant among animal
hosts.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
)-
and interleukin-4 (IL-4)-mediated immune pathways for the potentiation
of immunogenicity to a well-known Plasmodium falciparum
blood-stage malaria vaccine antigen, the major merozoite surface
protein 1 (MSP1) (8). Mice with
homozygotic disruption of the IFN- or IL-4 gene were immunized
with a recombinant MSP1 antigen (24) in several
previously described (18-20) adjuvant formulations. Past
studies have shown that protective immunity against MSP1 is primarily
antibody mediated (5, 8, 10), and thus we examined the
induction of anti-MSP1 antibodies by adjuvants. Our results revealed a
spectrum of requirements for cytokine-mediated pathways for
immunopotentiation, and such requirements were subjected to
dynamic influences among components of the adjuvant
formulations. Furthermore, utilization of immune pathways by an
adjuvant differed among mouse strains and subspecies.
View larger version (43K):
[in a new window]
FIG. 1.
ELISA antibody levels to MSP1-19 in BALB/c
IFN- 
/ and IFN-+/ mice immunized
with P2P30-MSP1-19 in liposomes, LA-15-PH/liposomes, B30-MDP/liposomes,
CFA, and alum. Tertiary 21-day sera at a 1/250 dilution were used; data
represent average OD ± SD from five mice per group.
View larger version (28K):
[in a new window]
FIG. 2.
Immunoglobulin isotype-specific antibody levels to
MSP1-19 in BALB/c IFN- / and IFN-+/
mice immunized with P2P30-MSP1-19 in various adjuvants. Tertiary 21-day
bleeds from five mice per group were used; data represent average
OD ± SD.
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MATERIALS AND METHODS |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Mouse strains.
BALB/c mice with homozygotic disruption of
the IFN- gene (IFN-/ mice; described in reference
9) were bred from heterozygotic breeding pairs
obtained from Genentech Inc. Genotyping for the wild-type and disrupted
IFN- genes was performed by PCR analyses of genomic DNA from tail
biopsies. Eight- to ten-week-old female IFN-/ mice
and their sex- and age-matched heterozygous littermates (IFN-+/) were used.
/ and C57BL/6 IL-4/ mice,
respectively. Eight- to ten-week-old females were used. Controls were
sex- and age-matched BALB/c or C57BL/6 mice (IL-4+/+).
Immunogen. The yeast-expressed, recombinant MSP1 protein corresponding to the C-terminal 19-kDa processing fragment of MSP1, P2P30-MSP1-19, has been previously described and shown to induce protective immunity in Aotus monkeys (24). The immunogen was a kind gift from David Kaslow (National Institute of Allergy and Infectious Diseases, National Institutes of Health). This clinical-grade antigen was produced and purified under GMP conditions.
Adjuvant formulations.
The five adjuvant formulations were
CFA or incomplete Freund's adjuvant (IFA), alum (Alhydrogel; Accurate
Chemical Science Corp., New York, N.Y.), multilamellar liposomes,
monophosphoryl lipid A (LA-15-PH) in liposomes (LA-15-PH/liposomes) and
muramyl dipeptide (B30-MDP) in liposomes (B30-MDP/liposomes). The
characteristics of these adjuvant formulations in inducing antibody
responses to MSP1 were described previously (18-20).
Multilamellar liposomes were prepared from
L-
-phosphatidylcholine dimyristoyl-cholesterol-dicetyl phosphate at a 1.0:0.75:0.11 ratio (19). These components
were dissolved in chloroform-methanol (4:1) and shell evaporated under vacuum on the wall of a Wheaton 50-ml rotoflask at 40 to 45°C. Liposomes were formed, after the addition of antigen, by adding 10 glass beads and shaking on ice for 30 min. To prepare
LA-15-PH/liposomes and B30-MDP/liposomes, LA-15-PH and B30-MDP were
first dissolved with the lipid components, and the liposomes were
formed as described above. Antigens were incorporated into the adjuvant
formulations as follows: for the CFA (or IFA) formulation, equal
volumes of antigen and CFA (or IFA) were emulsified; for the alum
formulation, alum was mixed with an equal volume of antigen and let
stand at 25°C for 30 min before use. For formulations containing
liposomes, antigen solutions were added to the rotoflask coated with
lipid components and were then entrapped in multilamellar liposomes as
the latter were formed.
Immunization.
BALB/c IFN-/ and
IFN-+/ mice (five per group) were immunized
intraperitoneally with P2P30-MSP1-19 (10 µg/mouse/injection)
formulated with the five adjuvant formulations described above. Three
injections were given at 4-week intervals. BALB/c IL-4/
and IL-4+/+ mice were similarly immunized. In addition,
C57BL/6 IL-4/ and IL-4+/+ mice were
immunized with P2P30-MSP1-19 in LA-15-PH/liposomes or with CFA or IFA.
Mice were bled 3 weeks after the tertiary immunization.
ELISAs. Mouse sera were assayed for anti-MSP1-19 antibodies by enzyme-linked immunosorbent assay (ELISA) as described elsewhere (18). Briefly, ELISA plates were coated with the recombinant MSP1 antigen at 1.0 µg/ml and blocked with 1% bovine serum albumin (BSA). Sera were diluted 1/250 in 1% BSA-0.5% yeast extract. Horseradish peroxidase-conjugated goat anti-mouse immunoglobulin G (IgG) plus IgM (Kirkegaard & Perry Laboratories, Gaithersburg, Md.) served as the secondary antibody. ELISA optical densities (ODs) were measured at 410 nm, after the addition of the peroxidase substrates H2O2 and 2,2'-azinobis(3-ethylbenzthiazolinesulfonic acid) (ABTS; Kirkegaard & Perry Laboratories). For immunoglobulin isotype analyses, peroxidase-conjugated rabbit anti-mouse IgG1, IgG2a, IgG2b, IgG3, and IgM (Zymed Laboratories Inc., South San Francisco, Calif.) were used as secondary antibodies. The Student t test was used to determine significant differences in OD levels; results are presented as average ± standard deviation (SD).
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RESULTS |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Immunogenicity of P2P30-MSP1-19 in IFN-/ and
IFN-+/ mice.
As shown in Fig. 1, P2P30-MSP1-19 in
liposomes showed a strong dependency for IFN- to induce
anti-MSP1-19 antibodies (IFN-/ versus
IFN-+/, P < 0.001). Addition of
LA-15-PH or B30-MDP to the liposome formulation abrogated the
dependency of IFN- for immunopotentiation, with no significant
changes in antibody levels. The absence of IFN- has little effect on
the levels of anti-MSP1-19 antibodies induced by CFA and alum.
Isotypes of anti-MSP1-19 antibodies in IFN-/ and
IFN-+/ mice.
In IFN-+/ mice,
both liposomes and LA-15-PH/liposomes potentiated a predominance of
Th1-type (IgG2a) antibodies (Fig. 2). However, only LA-15-PH/liposomes,
not liposomes, induced Th2-type (IgG1) anti-MSP1-19 antibodies in
IFN-/ mice. Freund's adjuvants produced isotypes
similar to those produced by LA-15-PH/liposomes in
IFN-/ and IFN-+/ mice, with a
predominance of IgG1. Anti-MSP1-19 antibodies induced by
B30-MDP/liposomes were exclusively IgG1, irrespective of the presence
or absence of IFN-. Thus, the ability of the liposomal components in
this formulation to induce IgG2a antibodies in
IFN-+/ mice was abrogated. Alum induced an
isotype profile very similar to that induced by B30-MDP/liposomes.
Immunogenicity of P2P30-MSP1-19 in BALB/c IL-4/ and
BALB/c IL-4+/+ mice.
For CFA, alum, B30-MDP/liposomes,
and liposomes, deficiency in IL-4 had little or no effect on the
immunogenicity of P2P30-MSP1-19 (Fig. 3).
However, IL-4/ mice receiving LA-15-PH/liposomes had
significantly lower anti-MSP1-19 antibody levels than controls
(P < 0.01), suggesting that this adjuvant requires
IL-4 for full immunopotentiating activity.
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Isotypes of anti-MSP1-19 antibodies in BALB/c IL-4/
and BALB/c IL-4+/+ mice.
Figure
4 details the isotype distribution of
anti-MSP1-19 antibodies induced by different adjuvants. With respect to
IgG1 (Th2-type) responses, results revealed three different effects of
IL-4 deficiency that were adjuvant dependent (Fig.
5). For LA-15-PH/liposomes and liposomes,
IL-4 knockout caused almost complete abrogation of IgG1 responses
(P < 0.001). By contrast, the potentiation of IgG1 by
B30-MDP/liposomes was clearly IL-4 independent. In CFA and alum groups,
IL-4 knockout caused partial but significant reductions in IgG1
(P < 0.01 for CFA or alum). The effects of IL-4
deficiency on the Th1-type (IgG2a) antibody response fell into two
categories (Fig. 6). For CFA,
LA-15-PH/liposomes, and liposomes, the production of Th1-type
antibodies was relatively independent of IL-4. By contrast, IL-4
knockout caused significant IgG2a or IgG2b production in the mice
receiving B30-MDP/liposomes and alum, while these isotypes were
undetectable or minimally produced in IL-4+/+ mice
(P < 0.001) (Fig. 4 and 6).
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Immunogenicity of P2P30-MSP1-19 in C57BL/6 IL-4/
and C57BL/6 IL-4+/+ mice.
Anti-MSP1-19 antibody
responses were unaffected by IL-4 knockout in CFA immunizations (Fig.
7). However, the antibody levels were
significantly lower in IL-4/ mice receiving
LA-15-PH/liposomes than in controls (P < 0.05) (Fig.
7).
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Isotypes of anti-MSP1-19 antibodies in C57BL/6
IL-4/ and C57BL/6 IL-4+/+ mice.
A
prominent effect of IL-4 knockout was the near-complete abrogation of
IgG1 antibodies after CFA immunization (Fig.
8). For LA-15-PH/liposomes, IgG1 was only
minimally detected in IL-4+/+ mice and undetectable in
IL-4/ mice (Fig. 8). There were also increases in IgG2b
production in IL-4/ mice for both adjuvants. Thus, the
IL-4-dependent pathway of anti-MSP1-19 IgG1 production was utilized in
C57BL/6 mice immunized with CFA but not LA-15-PH/liposomes. On the
other hand, the absence of IgG2a antibodies suggests that both
adjuvants did not utilize Th1-mediated pathways for the production of
anti-MSP1-19 antibodies.
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Basis for animal species differences in responses to
adjuvants.
Animal species differences in responses to an adjuvant
may result from disparate usages of cytokine-mediated immune pathways by an adjuvant. This is seen in the IL-4-regulated IgG1 responses induced by CFA and LA-15-PH/liposomes in BALB/c and C57BL/6 mice (Table
1). In the BALB/c background, CFA and
LA-15-PH/liposomes induced IgG1 responses, and these antibodies were
dominant in IFN-/ mice. The IgG1 responses induced
by both adjuvants were regulated by IL-4, as seen in BALB/c
IL-4/ mice. In the C57BL/6 background, only CFA, not
LA-15-PH/liposomes, was able to induce IL-4-dependent IgG1 responses.
The inability of C57BL/6 mice to produce appreciable levels of
anti-MSP1-19 IgG1 in response to LA-15-PH/liposomes was not due to an
inherent defect of this mouse strain since CFA readily induced these
antibodies in C57BL/6 mice.
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DISCUSSION |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The results of this study suggest that adjuvants utilize different
cytokine-mediated immune pathways to potentiate the immunogenicity of
an antigen and/or to uniquely affect the quality or specificity of
immune responses. Our results further suggest that the in vitro or in
vivo immunoactivities of adjuvants do not always predict or correspond
to the adjuvants' requirements of immune mediators for
immunopotentiation. For example, both LA-15-PH and B30-MDP induce
IFN-, -, and -
(22, 38, 39), but they do not depend on IFN- for the immunopotentiation of MSP1-19.
Comparisons of the Th1- and Th2-type antibodies offered clues to the
mode of action of these adjuvants. The induction of Th2-type (IgG1)
antibodies exclusively by B30-MDP/liposomes or predominantly by alum
would explain why a deficiency in IFN- (Th1 cytokine) may not
interfere with the immunopotentiation of these adjuvants via Th2
pathways. The enhancement of Th1-type (IgG2a) anti-MSP1-19 antibodies
by liposomes or LA-15-PH/liposomes is consistent with previous studies
which show preferential stimulation of this isotype during
immunizations with BSA in liposomes (32). Indeed, it has
been shown that ovalbumin (OVA) encapsulated liposomes preferentially stimulate production of IFN- from splenocytes (1). Our
results for liposome-mediated immunizations extend the role of IFN-
as an obligatory immune mediator for immunopotentiation. One such role may be the activation of macrophages as antigen-presenting cells
(12). Studies have shown a role of macrophages in the uptake
of liposome-trapped antigens (42), and this may require activation by IFN- (12). Since LA-15-PH/liposomes did not
depend on IFN- to potentiate anti-MSP1-19 antibodies, the
adjuvant may activate macrophages independent of IFN-. In this
regard, lipid A derivatives have been shown to activate
macrophages (39) and enhance the antigen-processing
capabilities of macrophages (43).
It is possible that compensatory immune mechanisms were utilized by
some adjuvants in IFN-/ mice for antibody
production. Recent studies suggest that IL-12 plays a major role in the
development of antibody responses (27). In these studies,
IL-12 exerts its influence via up-regulation of IFN- production,
resulting in enhanced IgG2a production. Most importantly, in the
absence of IFN-, IL-12 also potentiates antibody responses by
enhancing IgG1 and IgG2b production, perhaps via direct or indirect
effects on B cells. It is possible that LA-15-PH/liposomes or
other adjuvants in our study utilize IL-12 for antibody production in
IFN-/ mice. Since little or no anti-MSP1-19
antibodies were produced in IFN-/ mice immunized
with P2P30-MSP1-19/liposomes, this adjuvant formulation would not have
utilized such IL-12-mediated pathways.
In our IL-4 studies, only LA-15-PH/liposomes required IL-4 to
potentiate full immunogenicity to P2P30-MSP1-19. Thus, this adjuvant
may depend on IL-4 for activities additional to IgG1 responses. These
may be through IL-4's effects on B-cell growth and activation,
thymocyte maturation, and/or selective activation of monocytes
(2). There were two extremes in terms of dependency for IL-4
to induce IgG1 (Th2) to MSP1-19. The LA-15-PH/liposomes characterized
an absolute requirement for IL-4, while potentiation by
B30-MDP/liposomes was IL-4 independent. Several studies on the
immune responses to schistosomal, mycobacterial, and filarial proteins suggest that IL-13, IL-5, MCP-3, and/or B7-2 costimulation can
substitute for IL-4 in the generation of Th2 responses (6, 21, 26,
29, 37), and IL-13 has been shown to promote antibody isotype
switching (34). Whether B30-MDP/liposomes utilizes these immune mediators for IgG1 production remains to be determined. Equally
important is to determine if the IL-4-independent pathway(s) is
utilized by this adjuvant formulation principally or as a compensatory mechanism in the absence of IL-4. Immunization studies of
IL-4+/+ mice with genetic disruption of such pathways
may clarify these issues. Previous studies of IL-4/
mice immunized with OVA in alum or CFA show moderate decreases in
IgG1 responses compared to IL-4+/+ mice (3).
These results are similar to our findings with P2P30-MSP1-19 in alum or
CFA. This partial requirement of IL-4 for IgG1 response may reflect the
abilities of alum and CFA to drive both IL-4-dependent and
IL-4-independent pathways, as represented by LA-15-PH/liposomes and
B30-MDP/liposomes, respectively. However, disruption of
IL-4-dependent pathways in IL-4/ mice was not
fully compensated for by IL-4-independent mechanisms induced by CFA or
alum.
IL-4 may affect an adjuvant's ability to induce Th1-like, IgG2a
responses. In IL-4/ mice immunized with OVA in
alum, a vigorous IgG2a response was produced, whereas no detectable
IgG2a was observed in IL-4+/+ mice (3). Our
results for IL-4/ mice immunized with P2P30-MSP1-19 in
alum were in agreement with these studies. Moreover, our findings that
immunization with B30-MDP/liposomes was also able to induce IgG2a in
IL-4/ but not IL-4+/+ mice clearly
demonstrate that this is not a phenomenon peculiar to alum. Thus, the
immunopotentiating activities of adjuvants such as alum and
B30-MDP/liposomes may be regulated by the cytokine (e.g., IL-4) milieu
of the host.
Our findings regarding the IL-4-regulated IgG1 responses induced by CFA and LA-15-PH/liposomes in BALB/c and C57BL/6 mice suggest that animal species differences in response to an adjuvant may result from disparate usages of cytokine-mediated immune pathways by the adjuvant. We hypothesize that specific immune cells in one mouse strain which mediate a particular pathway may be more sensitive or permissive to stimulation by an adjuvant formulation than the analogous cell populations from another strain. On the other hand, the types of immune cells stimulated by an adjuvant may be different among mouse strains. Alternatively, nonimmune factors unique to the genetic background of one mouse strain may influence the activities of adjuvants.
This investigation focused on the antigen P2P30-MSP1-19. A logical question is whether the immune pathways utilized by an adjuvant vary with the particular immunogen. Studies have shown that for antigens that are weak or neutral in their abilities to polarize immune responses (e.g., Th1 versus Th2), adjuvants play a critical role in determining the profiles of immune responses (7). In these scenarios, the immune pathways utilized by an adjuvant may be identical or similar irrespective of the antigen used. On the other hand, some antigens possess intrinsic adjuvanticities, and administration of these antigens alone can polarize the profile of immune responses. The Leishmania protein LelF and the Schistosoma mansoni soluble egg antigens are examples which polarize for Th1 and Th2 responses, respectively (25, 31, 33, 36). Immunization with these antigens may enhance or limit the effectiveness of adjuvants, depending on whether the profiles of immune responses associated with the immunogen and with the adjuvant are opposing or complementary. Polarization of immune responses by an antigen may limit the availability of an immune pathway that is principally utilized by an adjuvant, which may then default to other pathways for immunopotentiation. These hypotheses are readily testable in appropriate gene knockout models. Finally, it is known that the affinity of an antigen for the T-cell receptor, the strength of T-cell receptor signalling, and the density of major histocompatibility complex class II ligands may influence immune response profiles (15, 40). Whether these factors affect the immune mediator usage by adjuvants remains to be determined.
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ACKNOWLEDGMENTS |
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We thank Shozo Kotani, Shoichi Kusumoto, and Daiichi
Pharmaceutical, Tokyo, Japan, for providing the adjuvants LA-15-PH and B30-MDP. We are also grateful to David Kaslow for providing the P2P30-MSP1-19 and MSP1-19 recombinant antigens and to Genentech Inc.
for providing the IFN-+/ mice.
This work was supported by Public Health Service grant AI31058.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Tropical Medicine, Leahi Hospital, 3675 Kilauea Ave., Honolulu, HI 96816. Phone: (808) 732-1477. Fax: (808) 732-1483. E-mail: ghui{at}hawaii.edu.
Editor: P. J. Sansonetti
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Infection and Immunity, November 1998, p. 5329-5336, Vol. 66, No. 11
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