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Journal of Virology, November 1999, p. 9609-9613, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Mucosal but Not Parenteral Immunization with
Purified Human Papillomavirus Type 16 Virus-Like Particles Induces
Neutralizing Titers of Antibodies throughout the Estrous Cycle
of Mice
Denise
Nardelli-Haefliger,1,*
Richard
Roden,2
Carole
Balmelli,1
Alexandra
Potts,1
John
Schiller,2 and
Pierre
De Grandi1
Department of Gynecology, Centre Hospitalier
Universitaire Vaudois, CH-1011 Lausanne,
Switzerland,1 and Laboratory of Cellular
Oncology, National Cancer Institute, Bethesda, Maryland
20892-40402
Received 12 May 1999/Accepted 23 July 1999
 |
ABSTRACT |
We have recently shown that nasal immunization of anesthetized mice
with human papillomavirus type 16 (HPV16) virus-like particles (VLPs)
is highly effective at inducing both neutralizing immunoglobulin A
(IgA) and IgG in genital secretions, while parenteral immunization induced only neutralizing IgG. Our data also demonstrated that both
isotypes are similarly neutralizing according to an in vitro pseudotyped neutralization assay. However, it is known that various amounts of IgA and IgG are produced in genital secretions along the
estrous cycle. Therefore, we have investigated how this variation influences the amount of HPV16 neutralizing antibodies induced after
immunization with VLPs. We have compared parenteral and nasal protocols
of vaccination with daily samplings of genital secretions of mice.
Enzyme-linked immunosorbent assay analysis showed that total IgA and
IgG inversely varied along the estrous cycle, with the largest amounts
of IgA in proestrus-estrus and the largest amount of IgG in diestrus.
This resulted in HPV16 neutralizing titers of IgG only being achieved
during diestrus upon parenteral immunization. In contrast, nasal
vaccination induced neutralizing titers of IgA plus IgG throughout the
estrous cycle, as confirmed by in vitro pseudotyped neutralization
assays. Our data suggest that mucosal immunization might be more
efficient than parenteral immunization at inducing continuous
protection of the female genital tract.
| |
TEXT |
The "high-risk" human
papillomavirus (HPV) types, most commonly type 16 (HPV16), are
etiologically linked to over 90% of cervical cancers (4).
Cervical cancer is the second leading cause of cancer deaths in women
worldwide, encouraging the development of a prophylactic vaccine to
prevent genital infection by these viruses. Vaccine development has
been hindered by the difficulty of virus propagation in culture and the
lack of animal models for the genital mucosatropic HPV types
(24). However, expression of the papillomavirus major capsid
protein L1 in mammalian, insect, and yeast cells or bacteria has been
shown to generate virus-like particles (VLPs) (15, 16, 18, 20, 26,
34, 36). Parenteral injection of VLPs elicits high titers of
serum neutralizing antibodies and protection from experimental
challenge with infectious virus in animal papillomavirus models
(7, 19, 34, 36, 41). Protection from experimental infection
with cottontail rabbit papillomavirus and canine oral papillomavirus by
passive transfer of immunoglobulin G (IgG) from immunized to naive
animals has been demonstrated for rabbits (7) and dogs
(41), respectively, indicating that cell-mediated effector
immune responses are not required for protection. However, to intercept
genital mucosal HPV, neutralizing antibodies must act at mucosal
surfaces. Protection of various mucosae is primarily mediated by
secretory IgA (sIgA), which is only induced upon antigen delivery to
mucosa-associated lymphoid tissues (21). However, in
addition to the locally produced sIgA, other Igs, mainly IgG, are also
present in genital secretions, where they are generally thought to
result from transudation through the vaginal epithelium (6, 25,
29, 44). Delivery of antigen through the nasal route of
immunization has been shown to be the most effective method of inducing
both sIgA and IgG in genital secretions of mice (2, 10, 12, 14,
17, 26, 28, 39), monkeys (35), and women
(3). In contrast, immunization by parenteral routes
(subcutaneous, intramuscular, or intraperitoneal) only leads to
specific IgG and no sIgA in genital secretions both for HPV VLPs
(2, 23) and for other antigens (5, 14, 27, 29,
43). Recently, we demonstrated that both nasal and parenteral
vaccinations with purified HPV16 VLPs induce HPV16 neutralizing
antibodies in genital secretions of mice (2). In these
experiments, the neutralizing activities of specific IgA and IgG were
similar, suggesting that IgG alone could be sufficient to protect the
genital tract. However, the amounts of IgA and IgG in genital
secretions are influenced by sex hormones and thus vary along the
estrous cycle in both rodents (30, 46, 47) and women
(5, 22, 37, 40, 42, 45). Here we have analyzed with mice how
these variations influence the outcome of parenteral or intranasal
vaccinations with purified HPV16 VLPs. Our results suggest that
induction of both antibody classes may be necessary to achieve
continuous protection of the female genital tract.
Ig content in vaginal washes of immunized mice varies along their
estrous cycle.
Twelve anesthetized female BALB/c mice were
immunized intranasally with three weekly doses of 5 µg of HPV16 VLP
and 5 µg of cholera toxin as described previously (2).
This mode of nasal vaccination allows inhalation of about one-third of
the inoculum (2), but for simplicity, it will be referred as
"nasal immunization" hereafter. In parallel, a total of 15 mice
were immunized parenterally by the subcutaneous or the intraperitoneal
route with multiple doses (three to four) of 1 or 5 µg of HPV16 VLPs.
Blood was obtained from all mice 2 to 3 weeks after the last
immunization, and then vaginal washes were taken daily for 5 consecutive days as described previously (17). Portions of
the vaginal washes were used to determine the stage of the estrous
cycle (1). Total and HPV16 VLP specific antibody contents in
serum and vaginal washes were determined by enzyme-linked immunosorbent
assay (ELISA) as described previously (17, 26). A total of
134 vaginal washes were analyzed: 38 were found in estrus, 33 in
metestrus, 48 in diestrus, and 15 in proestrus. The mean total IgA and
IgG contents at the different stages of the estrous cycle are shown in
Fig. 1. The largest amount of IgG and the
smallest amount of IgA occurred during diestrus, in agreement with data
reported by Gallichan and Rosenthal (13). This inverse
correlation in the amount of IgA and IgG was similarly observed in mice
immunized parenterally or nasally (data not shown). Overall, the amount
of IgA was higher than the amount of IgG, except during diestrus. This
is particularly striking when the IgG/IgA ratios are calculated for
each sample, thus avoiding the variations introduced by the sampling
method (data not shown). During estrus, there is about 10 times more
IgA than IgG in vaginal washes, and a positive IgG/IgA ratio is only
found during diestrus (2 times more IgG than IgA). We therefore
determined how these variations influenced the specific antibody
response induced by vaccination.
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FIG. 1.
Igs in vaginal washes of immunized mice along the
estrous cycle. The mean total IgG and IgA in vaginal washes collected
from mice at different stages of the estrous cycle are shown. E,
estrus; M, metestrus; D, diestrus; P, proestrus.
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|
Variations in anti-HPV16 VLP antibodies in vaginal washes of mice
immunized intranasally or parenterally along the estrous cycle.
In
contrast to mucosal immunization, parenteral immunization can only
induce antibodies of the IgG isotype in vaginal washes (2, 5, 14,
23, 27, 29, 43). Here we have compared two groups of mice
immunized parenterally or intranasally with purified HPV16 VLPs (see
above). For technical reasons, we have used cholera toxin for nasal
immunization to increase the titers of the systemic (5× to 10×) and
mucosal (2× to 5×) antibody responses (2). Clearly such an
adjuvant is toxic in humans, but it is likely that a similar effect is
achievable with either higher doses of VLPs or detoxified mucosal
adjuvants (8, 11). This allowed us to use low VLP nasal
doses (5 µg) in mice to induce specific titers of antibodies in serum
and secretions (IgG) similar to parenteral immunization and high enough
to allow neutralization assays to be performed. The mean titers of
anti-HPV16 VLP IgG in serum were indeed similar in the two groups of
mice, with mean titers of 205,000 for the mice immunized parenterally
and 225,000 for the mice immunized intranasally. The titers of HPV16
VLP specific IgA and/or IgG induced by parenteral or intranasal
immunization in the vaginal washes were grouped according to their
estrous stage. The mean titers are shown in Fig.
2. The variation among specific antibody
titers along the estrous cycle was similar to the variation observed
when total IgG or IgA was considered (Fig. 1), although, as expected,
no or barely detectable specific IgA was induced in mice immunized
parenterally. The specific IgG titers in the vaginal washes were very
similar in the two groups of mice, with a maximal mean titer of 150 during diestrus. This probably reflected the serum specific IgG titers,
which were also similar in these mice (205,000 and 225,000). This is in
agreement with the hypothesis that specific IgG in vaginal washes is
derived mainly from the serum by transudation, a phenomenon that varies during the estrous cycle, probably along with changes in the
permeability of the genital mucosa, while IgA is produced locally
(6, 25, 29, 44).
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FIG. 2.
Anti-HPV16 VLP antibodies in vaginal washes of mice
immunized intranasally (A) or parenterally (B) with purified HPV16
VLPs. The mean anti-HPV16 VLP IgG and IgA titers, expressed as the
reciprocal of the highest dilutions that yielded an optical density at
492 nm four times that of preimmune samples, in vaginal washes
collected from mice at different stages of the estrous cycle are shown.
E, estrus; M, metestrus; D, diestrus; P, proestrus.
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|
To confirm this, we have determined the number of total or specific
antibody-secreting cells (ASCs) in the genital tract by
enzyme-linked
immunospot assay (
9,
38). Briefly, single-cell
suspensions
of uterine horns and vagina-cervix were obtained by
enzymatic
digestions (thermolysin at 0.25 mg/ml, followed by collagenase-dispase
at 1 mg/ml and DNase at 2 mg/ml), followed by filtration through
50-µm-pore-diameter nylon filters. Maxisorb plates (NUNC) were
coated
with 70 ng of purified HPV16 VLPs or 100 ng of rabbit anti-mouse
Igs
(
17,
26), and spots representing individual ASCs were
visualized by alkaline phosphatase-conjugated secondary antibodies
revealed with 5-bromo-4 chloro-3-indolyphosphate (BCIP)
substrate.
ELISPOT analysis of total Ig-secreting cells (SCs) performed
with
11 mice in diestrus and 4 mice in estrus revealed that, in
general,
more ASCs were found in uterus than in vagina-cervix (Fig.
3).
This is in agreement with the
reported higher numbers of plasma
IgA cells in the uterine horn and
body (
30,
31). However,
we detected more IgA SCs during
diestrus than during estrus, while
the opposite was reported when
plasma IgA cells were considered
(
32). The higher level of
secretory component reported during
estrus in rodents (
46)
may finally account for the large amount
of IgA measured in secretions
during estrus. Unexpectedly, high
numbers of IgG SCs were found in both
uterus and vagina-cervix,
while IgA SCs appeared to be less abundant.
However, high numbers
of HPV16 VLP specific ASCs were only found after
intranasal immunization
both in uterus and in vagina-cervix. These ASCs
were of the IgA
isotype and represented between 2 and 15% of the total
IgA SCs
detected (Table
1), while few if
any specific IgG SCs were detected
after intranasal (Table
1) or
parenteral immunization (below
0.1% of the total IgG SCs [data not
shown]). Altogether, our data
suggest that in contrast to the specific
IgA, only a few specific
IgGs might be produced locally in the genital
tract, while the
majority are derived from the serum.
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FIG. 3.
Ig SCs in the genital tract of immunized mice sacrificed
at estrus or diestrus. The mean numbers of IgA or IgG
SCs/106 cells are indicated separately for uterus and
vagina-cervix.
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|
Neutralization efficacy of the vaginal washes collected along the
estrous cycle of mice immunized intranasally or parenterally.
We
had previously shown that anti-HPV16 VLP antibodies at titers of 64 and
98, respectively, for IgA plus IgG and IgG alone resulted in 50%
neutralization in the HPV16 pseudotyped in vitro neutralization assay
(2, 33). However, the mean anti-HPV16 VLP IgG titers in
vaginal washes after parenteral immunization only reached titers over
100 when the samples were collected during diestrus (Fig. 2),
suggesting that only at that time might the vaginal washes be fully
neutralizing. In contrast, although similar specific IgG titers were
found after intranasal immunization, titers of anti-HPV16 VLP IgA over
100 are found at all stages of the estrous cycle, suggesting that full
neutralization could occur at all times. To confirm this, vaginal
washes were pooled from mice at same estrous stage after either
intranasal or parenteral immunization and then analyzed in the
pseudotyped in vitro neutralization assay (33). To perform
the neutralization assays, the vaginal washes must be diluted with
pseudovirions. Therefore, in order to achieve relatively high final
titers of specific antibodies in the neutralization assays, we have
pooled vaginal washes harboring the highest titers of specific
antibodies. This resulted in different volumes and titers of specific
antibodies in the pooled secretions pending the estrous stage and the
route of immunization. The final anti-HPV16 VLP IgA or IgG titers
achieved in the neutralization assays with the resulting neutralization
efficacies are shown in Table 2.
Relatively high anti-HPV16 VLP titers (84 to 182) could be achieved
with three pools of vaginal washes (diestrus, metestrus, and proestrus)
collected from mice immunized intranasally, resulting in almost full
neutralization in the assay. The lowest neutralization efficacy (71%)
obtained with vaginal washes collected in estrus reflected the lowest
final titers of IgA (a titer of 61) achieved in this pool of sample and
also the lowest mean titer of specific IgA plus IgG (a titer of 172)
measured after intranasal immunization (Fig. 2). In contrast, only with
the samples collected during diestrus and metestrus after parenteral
immunization could we achieve titers of specific IgG (titers of 63 and
41, respectively) that resulted in partial neutralization (67 and
61%), while the two other vaginal wash pools were not neutralizing.
Overall, as we had previously reported (2), the results
obtained with in vitro neutralization faithfully reflected the titers
of anti-HPV16 antibodies measured by ELISA. This confirmed that only
intranasally immunized mice harbor titers of specific antibodies in
vaginal washes which could fully neutralize HPV16 all along the estrous cycle.
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TABLE 2.
Neutralization efficacy of vaginal washes pooled from
mice immunized intranasally (tubes 1 to 4) or parenterally (tubes 5 to
8) with purified HPV16 VLPs
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|
Whether the induction of sIgA in addition to IgG is important to
protect a woman's genital tract against HPV infections is
not yet
clear. Variation in Igs along the menstrual cycle has
also been
observed in women (
5,
22,
37,
40,
42,
45),
although the data
reported with different sampling techniques,
genital fluids, and
periods of the menstrual cycle sampled do
not permit a definitive
conclusion to be drawn. However, our data
from mice strongly suggest
that a mucosal route of immunization
with the additional induction of
specific sIgA may overcome the
variations in IgG content which also
occur along the menstrual
cycle in
women.
| |
ACKNOWLEDGMENTS |
This work was supported by Fonds de Service of the Department of
Gynecology and Swiss National Funds 31-52892.97 to D.N.-H. and by the
intramural program of the National Cancer Institute.
| |
FOOTNOTES |
*
Corresponding author. Mailing address:
Département de Gynécologie, c/o Institut de Microbiologie,
Bugnon 44, 1011 Lausanne, Switzerland. Phone: 21/314 40 81. Fax: 21/314
40 95. E-mail: DNARDELL{at}hola.hospvd.ch.
| |
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0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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