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Gynecologic Oncology 110 (2008) S1 – S10
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Immune response to human papillomavirus after prophylactic vaccination
with AS04-adjuvanted HPV-16/18 vaccine: Improving upon nature
Tino F. Schwarz a,⁎, Oberdan Leo b,1
a
b
Central Laboratory and Vaccination Centre, Stiftung Juliusspital Würzburg, Juliuspromenade 19, 97070 Würzburg, Germany
Laboratoire de Physiologie Animale, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, 6041 Charleroi (Gosselies), Belgium
Received 12 March 2008
Abstract
An AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine has demonstrated excellent efficacy for up to 6.4 years in preventing related
persistent infections and cervical precancerous lesions in both Phase II and Phase III clinical trials. The immune responses induced by HPV
vaccination are different to those after natural infection. The virus has learned to largely evade our immune system through centuries of coevolution with the consequence that the immune responses after natural infection, aiming to control or eradicate the virus, are attenuated.
However, the AS04-adjuvanted HPV prophylactic vaccine, designed with a new Adjuvant System approach, is able to improve upon the natural
immune responses to the virus as it induces strong and sustained neutralizing antibody levels that are several times higher than after natural
infection, while creating immune memory through higher frequency of memory B cells. These immunological effects represent the basis for the
protection afforded by the AS04-adjuvanted HPV-16/18 vaccine and its observed long-term efficacy against development of precancerous lesions
to prevent cervical cancer.
© 2008 Elsevier Inc. All rights reserved.
Keywords: Cervical cancer; Vaccine; Human papillomavirus; Immune response
Introduction
Cervical cancer is a significant cause of morbidity and
mortality in women globally. It is estimated that up to 80% of
women will acquire a human papillomavirus (HPV) infection in
their lifetime [1]. Although most adult women recover
completely from their HPV infection, about 5–10% will not
clear the virus and develop persistent infection. Persistent
infection with an oncogenic type of HPV is an important early
precursor event in the progression to cervical precancerous
lesions and cervical cancer [2–5].
As many as 15 HPV types have been identified as being of
oncogenic risk to the cervix. Of these, HPV-16 and -18 are most
commonly found in cancerous cervical tissue [6], accounting
⁎ Corresponding author. Fax: +49 931 393 2268.
E-mail addresses: [email protected] (T.F. Schwarz),
[email protected] (O. Leo).
1
Fax: +32 2 650 98 60.
0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2008.05.036
for 70% of the cervical cancer cases worldwide [7,8]. HPV-45
and -31 represent the third and fourth most prevalent types
responsible for an additional 10% of all cervical cancer cases,
while the risk associated with the remaining oncogenic HPV
types is lower. Studies have also shown that HPV persistent
infection occurs at a higher percentage with HPV-16 than with
other oncogenic HPV types [9] and that the risk of progression
to cervical cancer is higher for HPV-16, -18 and -45 than for
other HPV types [8].
Despite the high natural HPV infection rate in adolescent
female populations, most HPV infections of the cervix are
asymptomatic, with reported clearance rates of approximately
30% at 6 months and approximately 50% at 12 months [10].
The degree of protection and the duration of immunity induced
by natural incident infection are not known, but only 50–60%
of women develop serum antibodies to HPV after natural
infection [11], and some of these women are still susceptible to
re-infection with the same HPV type. As a result of the
asymptomatic pattern of HPV infection in women and the
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T.F. Schwarz, O. Leo / Gynecologic Oncology 110 (2008) S1–S10
lifelong risk of being infected, the primary goal for an HPV
vaccine is to ensure long-term protection.
If the immune system fails to clear or control an incident
infection with oncogenic HPV, the infection may become
persistent. A persistent infection is generally defined as the
continued detection of viral DNA of the same HPV type in the
cervix for at least 6–12 months [12,13] and can lead to the
development of high-grade cervical intraepithelial neoplasia
(CIN2/3) that can progress to invasive cancer. The risk of
squamous intraepithelial lesion or CIN development following
persistent HPV-16 or -18 infection is high (odds ratio of 169 for
HPV-16/18) [14]. Therefore, in order to provide strong and
sustained protection against incident and persistent infections
with HPV-16 and -18 and associated precancerous lesions,
prophylactic HPV vaccination needs to improve on natural
immunity. The aim of HPV vaccination is to induce a first line
of immunological defense by eliciting large amounts of
antibodies that will be able to prevent the virus from entering
the cells at the site of infection.
The human papillomavirus: a virus which evades host
defenses
Classical chronic viral infections, such as those caused by the
hepatitis B virus (HBV) or herpes simplex virus (HSV), share
persistent viremia during the course of the infection. HBV
primarily causes a systemic infection, while HSV causes both
mucosal and systemic infection. The rapid presence of viral
particles in the bloodstream allows the immune system to
recognize and mount a rapid and strong response directed against
the pathogen, including both the secretion of high levels of
circulating antibodies able to neutralize and control the pathogen
and a cellular response. In addition, for most viral infections, time
of disease coincides with the time of productive infection.
HPV infection and the subsequent immunological consequences differ from this classical view of viral infections. HPV
does not cause viremia or systemic infection. The virus has a
specific tropism either for the squamous epithelium of the skin
or mucosal sites. After transmission, mainly by sexual contact,
HPV remains located in the epithelial cells of the mucosa.
Lacking a bloodstream phase, HPV is barely exposed to the
systemic immune system, and antibody levels induced after
natural infection are very low and probably not protective
during primary infection; they increase only in individuals with
persistent infections, i.e. at later stages of the disease [15].
The natural infectious cycle of genital HPV is adapted to the
differentiation program of the cells it infects. HPV infects basal
keratinocytes that mature vertically through the epithelium to
the cervical lumen. In infected cells, viral protein expression
and keratinocyte differentiation are controlled in a coordinated
fashion, such that the mature virions are produced only in the
most superficial layers of the epithelium. As these virus-laden
cells desquamate, the viruses are released into the environment
[16]. The time from infection to viral release is approximately
3 weeks, which coincides with the time for basal keratinocytes
to undergo complete differentiation, desquamation and natural
cell death [17].
The adaptation of HPV to the differentiation program of
keratinocytes is an important mechanism to evade the host's
immunity. The virus by itself is not cytolytic for the superficial
cells. Rather, the fully differentiated epithelial cells undergo a
programmed cell death and desquamation. This natural cell death
does not present a danger signal to the immune system and
therefore is not accompanied by inflammation. Moreover, HPV
proteins that would be recognized as foreign by the immune
system are expressed only at low levels and are not secreted and
hence are not visible to the immune system [18–20]. As a result of
these and other host evasion mechanisms, the local innate immune
responses aiming to control or eradicate the virus are attenuated.
HPV and the immune system
How the immune system fights against a pathogen
Upon natural infection, the host immune system generally
employs both innate and adaptive immunity to recognize and
fight foreign agents (Fig. 1). The innate immune system is able
to provide early and non-specific protection against a large
variety of pathogens. This response is stereotyped in nature, and
does not intensify following repetitive infectious events. In
contrast, adaptive immunity, encompassing the humoral and the
cell-mediated immune responses, generates pathogen-specific
effector cell responses and provides pathogen-specific immunological memory, allowing a more rapid and vigorous response
upon a second encounter with the same pathogen.
Local inflammation is the principal marker of the innate
immune response, which is activated by local cell death and injury
at the site of infection. It involves the recruitment of phagocytic
cells (neutrophils, dendritic cells and macrophages) and the release
of soluble mediators (such as cytokines and complement).
Dendritic cells serve as the bridge between the innate and adaptive
immune responses (Fig. 1). These cells take up and process
microbial antigens while migrating to secondary lymphoid organs,
such as the draining lymph nodes, where they become fullyfunctional antigen-presenting cells (APC) and interact with T
helper lymphocytes that are part of cell-mediated immunity (CMI).
T helper lymphocytes are able to regulate the two different arms of
the adaptive immune system. They can promote differentiation of
cytotoxic T lymphocytes, a class of effector T cells able to migrate
to the infected site and kill pathogen-infected cells. A fraction of
the T helper lymphocytes and of the cytotoxic T lymphocytes
becomes memory T cells and forms the T cell memory pool.
T helper lymphocytes also activate the humoral arm of the
immune system, which results in the production of pathogenspecific antibodies (Fig. 1). Although the immune response
needed for different pathogens may vary, a strong antibody
response is the cornerstone for protection against most viral
diseases. Activation by T helper lymphocytes induces the
differentiation of B lymphocytes into plasma cells that will
secrete pathogen-specific antibodies able to bind the extracellular pathogen, flagging it for destruction by the phagocytic
cells. The antibodies may also neutralize the virus by binding to
the viral capsid proteins, thereby preventing the virus from
entering the host cells. Some plasma cells become long-lived
T.F. Schwarz, O. Leo / Gynecologic Oncology 110 (2008) S1–S10
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Fig. 1. Overview of the innate and adaptive immune responses. Dendritic cells capture and process antigen at the site of infection and are activated as part of the innate
immune response. This induces their migration to local lymphoid tissue and their maturation into efficient antigen-presenting cells (APCs). Naïve T lymphocytes
recognize foreign antigen that has been processed into short peptides and presented by APCs. This results in T helper cell activation and secretion of a variety of small
proteins and cytokines. T helper cells support the humoral response, facilitating the differentiation of B lymphocytes into antibody-secreting plasma cells or memory B
cells. The plasma cells secrete antibodies such as IgA and IgG, and memory B cells remember the foreign antigen for faster antibody production upon re-infection with
the same antigen. Another subset of the T helper cells promotes the cell-mediated response allowing the activation of cytotoxic T lymphocytes and generation of
memory T cells. They also further activate macrophages and natural killer cells of the innate immune response. Cytotoxic T cells and natural killer cells are able to
migrate to the infected site and kill pathogen-infected cells.
plasma cells and continuously secrete antibodies to maintain a
minimum level of protective antibodies long after the first
contact with the pathogen. A fraction of B cells differentiates
into memory B lymphocytes to form the humoral memory,
which ensures that a rapid and amplified antibody response is
initiated upon re-infection by the same pathogen.
Natural immune response against HPV infection
Despite the ability of HPV to evade the host's immune system
and to down-regulate innate immunity, a primary infection is
naturally cleared in approximately 90% of cases. The precise
sequence of immune events following HPV infection in the
cervical tract is not fully understood, but it is clear that first innate
and cell-mediated immunity and then humoral immunity play a
role in the immune response at the site of HPV infection in the
genital tract [21–23]. A cell-mediated immune response (effector
T lymphocytes) directed against the early E2 and E6 HPV proteins
occurs first, as reflected by the infiltration of specific helper and
cytotoxic T lymphocytes, macrophages, and the local production
of proinflammatory cytokines [21,24,25]. Approximately
8 months after infection, low levels of neutralizing antibodies to
the major capsid protein L1 may appear in the serum of infected
individuals, and specific IgG and secretory IgA are found locally
in the cervical mucosa, but at very low levels [23,26,27].
Antibodies generated in response to a persistent primary infection
may prevent successive rounds of auto-inoculation within the
female genital tract. Induction of CMI would be expected to
prevent further outgrowth and eventually induce regression of
individual lesions. Although HPV infection can lead to
seroconversion (induction of measurable specific antibodies in
the serum), in some subjects antibody levels after natural infection
appear to be insufficient for long-term protection [28].
Vaccine-induced immune response against HPV infection
The first challenge for an HPV vaccine is to demonstrate
protective efficacy through a systemic immune response for a
virus that enters only via the mucosal route and remains
localized there. The mechanism by which vaccine protects
against HPV infection has not been fully elucidated, but
experimental data have shown that high levels of HPV-specific
neutralizing serum antibodies are key for reliable protection
against HPV infection [29–31]. Neutralizing antibodies are also
considered in a WHO publication “to be the major basis for
protection by VLP-based vaccines in humans” [32]. Not only
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are anti-HPV antibodies important, but some experimental data
also indicate that they are sufficient to afford protection. Indeed,
passive transfer of serum or IgG from vaccinated animals to
naïve animals has been found to confer protection against
animal papillomavirus infection [31,33]. HPV transmission and
infection occur at the cervical epithelium, where HPV can be
counteracted by local IgG, the main immunoglobulin present in
the female genital tract. In vaccinated subjects, antibodies
represent the first line of defense. They are already present at the
time of exposure. These neutralizing antibodies are not
produced locally, but transudate or exudate from serum to the
cervical mucus (Fig. 2) [34–37]. The antibodies must reach the
cervical mucosa, but they also need to be present at sufficient
levels and in a timely and spatially orchestrated manner to
neutralize the virus before it enters the cells.
However, the protective level of anti-HPV antibody is not
known. After natural infection, some seroconverted individuals
have become infected with the same type of HPV [28],
indicating that the antibody levels induced after primary
infection may not always be sufficient for long-term protection.
Although the minimum level for protection can only be
established when a sufficient number of breakthrough cases
are observed through clinical trials, a direct correlation between
antibody levels and protection is intuitively obvious. In that
respect, antibody titers close to or inferior to those induced by
natural HPV infection may not be sufficient. A high level of
specific antibodies in the cervical mucosa at the time of HPV
exposure is the best guarantee for protection.
After immunization, exposure of individuals to the same HPV
type is not likely to significantly boost the antibody level, since the
epithelial localization and invasion process of the virus will make
it invisible to the pool of memory cells at an early stage. Notably, a
boost of the systemic response has been demonstrated after
parenteral antigen challenge only and not after re-infection [38].
Therefore, to offer continued protection against oncogenic HPV
types, vaccination should induce not only a strong but also a
sustained antibody response at the systemic level and at the site of
primary infection [39–41]. This does not exclude that vaccineinduced CMI also plays a role in viral defense of immunized
individuals. Enhanced vaccine-induced CMI would be expected
to function in support of antibody production and maintenance of
memory B cells, and not as an independent effector mechanism.
Traditionally, the induction of memory B cells is considered a
crucial factor for the long-term efficacy of vaccine-induced
protection [41]. Indeed, a sustained specific antibody production
does not only reflect the generation of long-lived plasma cells but
also the induction of memory B cells able to regenerate the pool of
antibody-secreting cells. In this respect, recent studies have
demonstrated a positive correlation between the frequency of
antigen-specific memory B cells and antigen-specific serum
antibody levels in studies of vaccines against tetanus toxoid [42],
smallpox [43] and hepatitis B [44]. Prophylactic vaccination
against HPV-16/18 with an AS04-adjuvanted vaccine has been
shown to induce high frequencies of memory B cells [39]. This
may be the basis for the generation of long-lived plasma cells and
hence the high and sustained antibody responses observed up to
6.4 years for both HPV-16 and -18 after VLP vaccination [45–48].
Clinical results after AS04-adjuvanted HPV-16/18
vaccination
HPV prophylactic vaccine
The most successful approach for a prophylactic HPV
vaccine has been the use of non-infectious virus-like particles
(VLPs), composed of the major virus capsid protein L1. Genetic
engineering techniques have been utilized to express these
structural proteins, which undergo self-assembly to form empty
Fig. 2. Transudation and exudation of serum antibodies to the site of HPV infection. The transudation process involves the transfer of IgG from the intravascular
compartment into the genital tract through ultrafiltration caused by an imbalance of the hydrostatic forces across the walls of the microcirculation [75]. In contrast,
exudation is the slow escape of fluid from damaged blood vessels [75] at sites of microtrauma, such as those that occur through intercourse [36,76]. Cervical cancers
usually develop at a metaplastic zone between the squamous and columnar epithelium in the cervix known as the transformation zone [75]. It is at this site that IgG
neutralizing antibodies are thought to transudate across the cervical epithelium [41].
T.F. Schwarz, O. Leo / Gynecologic Oncology 110 (2008) S1–S10
viral capsids. The L1 VLPs have been shown to be
morphologically and antigenically similar to authentic virions.
Three distinct animal model systems have all demonstrated that
L1 VLPs are potent immunogens that can induce protection
against virus challenge and associated lesions. Current HPV
vaccines for the prevention of cervical cancer have demonstrated very promising efficacy results in recently completed
and ongoing clinical trials [38,46,47,49–54].
The L1 VLPs are usually formulated with vaccine adjuvants to
enhance the antigen-induced humoral and cellular immune
responses. There are two vaccines for the prevention of cervical
cancer, which have recently been licensed. One of these two
vaccines, Cervarix™ from GlaxoSmithKline, contains L1 VLPs
for HPV types 16 and 18 designed for the prevention of related
infection and precancerous lesions. The second vaccine,
Gardasil™ from Merck, contains L1 VLPs for HPV types 6,
11, 16 and 18 designed for the prevention of precancerous lesions
caused by HPV-16/18 and genital warts caused by HPV-6/11.
Gardasil™ is formulated with an aluminum hydroxy-phosphate-based adjuvant, whereas Cervarix™ is formulated with an
Adjuvant System referred to as AS04, which contains a
combination of aluminum hydroxide and the immunostimulant
MPL (3-O-desacyl-4′-monophosphoryl lipid A). The AS04
Adjuvant System has been utilized with two other vaccines
against viral diseases. The first is a licensed HBV vaccine for
hemodialysis patients. The second is a candidate vaccine against
herpes simplex virus (HSV) infection. The AS04-adjuvanted
HBV vaccine was superior to the corresponding vaccine
adjuvanted with aluminum salt alone in terms of its capacity to
induce a strong and sustained immune response, e.g. a higher
number of subjects being protected and/or a more sustained
protection in the long term [55,56]. Evaluation of the efficacy of
the AS04-adjuvanted HSV vaccine showed significant protection
(73%) against disease in women who were seronegative for HSV1 and -2 before vaccination [57]. AS04-containing vaccines have
been administered to more than 30,000 subjects, being generally
well tolerated with an acceptable safety profile [57–60].
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While aluminum salts have been used extensively as
adjuvants in vaccines, their mechanism of action is not fully
understood and they have not been the optimal choice for
several vaccines in development, such as malaria and HSV
candidate vaccines [60]. The MPL component of the AS04
Adjuvant System represents an efficient answer to this problem,
as this compound is not only able to promote an antibody
response but also efficiently augments the cell-mediated arm of
an immune response. MPL is the non-toxic form of the cell wall
lipopolysaccharide of the gram-negative Salmonella minnesota
R595 strain. MPL potentiates specific immune responses to
vaccination and has been shown to act through innate immune
mechanisms, particularly by activating dendritic cells [61].
When compared with vaccine formulated with aluminum
hydroxide alone, although both types of vaccines induced a
long-lasting humoral (antibody) response persisting for at least
3.5 years in vaccinated women, vaccination with the AS04
Adjuvant System induced consistently higher antibody levels
throughout the observation period [39] (Fig. 3). In addition,
AS04 elicited an increased frequency (2.2–5.2-fold) of HPV-16
and HPV-18 L1 VLP-specific memory B cells when compared
with aluminum salt formulations [39]. In this respect, inclusion
of AS04 in the vaccine formulation will enhance the immune
response leading to high antibody levels and high frequency of
memory B cells.
Serological response to HPV vaccine
In an ongoing extended follow-up study (580299/007) of an
initial Phase IIb primary efficacy trial of the AS04-adjuvanted
cervical cancer vaccine in an HPV-16/18 naïve population
(580299/001) [46], a strong and sustained anti-HPV-16/18
neutralizing antibody response was induced for up to approximately 5.5 years post-vaccination in young women aged 15–
25 years (Fig. 4) [45,48,62,63]. Seropositivity for both HPV-16
and -18 neutralizing antibodies was ≥98% and was sustained
throughout this period. At 63–64 months following first
Fig. 3. Neutralizing antibodies against HPV-16 and -18 induced by vaccination. When compared with HPV-16/18 vaccine formulated with aluminum hydroxide alone,
the vaccine formulated with AS04 Adjuvant System induces higher and long-lasting immune response in humans in terms of neutralizing serum antibodies specifically
directed against V5 or J4 epitopes (modified from [39]). V5 and J4 are the important neutralizing/conformational epitopes of HPV-16 and -18, respectively.
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T.F. Schwarz, O. Leo / Gynecologic Oncology 110 (2008) S1–S10
Fig. 4. Geometric mean titers (and 95% confidence intervals) of (A) anti-HPV-16 and (B) anti-HPV-18 total IgG antibodies in women aged 15–25 years included in a
Phase II study (580299/007) of AS04-adjuvanted cervical cancer vaccine during a 5.5 year follow-up [69]. Levels of naturally-acquired anti-HPV-16 antibodies
[29.8 EU/mL (95% CI: 28.5–31.0)] and HPV-18 antibodies [22.6 EU/mL (95% CI: 21.6–23.6)] are shown by a horizontal line. Geometric mean titers for natural
infection were obtained from baseline serum samples of subjects included in a Phase III study (580299/008) who were seropositive and HPV DNA negative for the
respective HPV type [51].
vaccination, geometric mean titers (GMTs) for total anti-HPV-16
and anti-HPV-18 IgG, when compared with baseline GMTs
observed in subjects enrolled in a Phase III study (580299/008)
who had cleared HPV-16 or -18 infection (seropositive and DNA
negative) [51], were at least 11-fold higher for both types at any
time point. According to a mathematical modeling study, the
vaccine is predicted to generate sustained longevity of anti-HPV16 and -18 antibody titers, both remaining substantially above
those associated with natural infection and lasting for several
decades in young women aged 15–25 years [64].
Substantial long-term vaccine efficacy was observed against
HPV-16 and/or HPV-18 endpoints, including incident infection
(98% [95% CI: 89–100]), 6-month persistent infection (100%
[95% CI: 81–100]), 12-month persistent infection (100% [95%
CI: 54–100]), and cytological abnormalities greater than or
equal to atypical squamous cells of undetermined significance
(100% [95% CI: 85–100]) [63]. Vaccine efficacy has also been
evaluated in a large, international, Phase III trial (580299/008)
conducted in a broad population of young women aged 15–
25 years [51]. Vaccinees were uninfected with HPV-16/18 but
possibly infected with other oncogenic HPV types or had current
or previous low-grade cytological abnormalities prior to
vaccination. In an interim analysis, vaccination exhibited high
prophylactic efficacy (up to 100%) against CIN grade two
lesions or worse that were associated with HPV-16/18.
Vaccine-induced neutralizing antibodies
Preclinical models have demonstrated the critical role of
neutralizing antibodies in protecting against papillomavirus
infection [31,33,65,66]. By preventing persistent HPV-16/18
infection, these antibodies are thought to efficiently prevent
cervical cancer development in vaccinated women. It is
noteworthy that while total antibody responses can be easily
determined by classical antigen-binding enzyme-linked immunosorbent assay (ELISA), neutralizing antibodies can only be
T.F. Schwarz, O. Leo / Gynecologic Oncology 110 (2008) S1–S10
identified using pseudovirion-based neutralization assays
(PBNA). Anti-HPV-16 and -18 neutralizing antibody titers
were specifically assessed in a subset of women throughout the
extended follow-up study (580299/007) [62]. At least 98% of
all vaccinees had detectable HPV-16 and -18 neutralizing
antibody responses that were maintained up to 5.5 years
following first vaccination. The kinetic profile observed for
GMTs of neutralizing antibodies against HPV-16 and -18 was
similar to that seen with GMTs of total IgG. Furthermore, a high
correlation was observed between antigen-binding ELISA and
PBNA at all time points up to 5.5 years, indicating that GSK's
antigen-binding ELISA is a valuable tool for measuring
vaccine-induced immune response. Taken together with the
total antibody ELISA data described above, these findings
suggest that the AS04-adjuvanted cervical cancer vaccine
elicits high-level, high-quality and long-lasting neutralizing
antibody responses in young women aged 15–25 years.
S7
Fig. 5. Proposed mechanisms by which vaccine-induced neutralizing antibodies
protect against HPV infection. Protection against a new infection, infection at
another site, or reduced viral load after shedding of viral particles.
Vaccine-induced antibodies transudate to the cervical mucosa
Local and systemic antibody responses play an important
role in HPV vaccine-induced responses, as demonstrated by
AS04-adjuvanted cervical cancer vaccine, which has been
shown to induce high levels of HPV-16 and -18 antibodies in
serum and cervicovaginal secretions (CVS) for at least
24 months following the first vaccine dose in females aged
15–55 years [67]. In all age groups, a strong correlation was
observed between serum and CVS antibody titers for both HPV16 and HPV-18 [67]. Thus, systemic vaccination with AS04adjuvanted vaccine is able to induce serum neutralizing IgG
antibodies that transudate to the site of HPV infection in
sufficiently high concentrations to bind HPV particles, and may
contribute to vaccine efficacy [67]. These results highlight the
important relationship between antibody levels at both
serological and mucosal sites for prevention of infection in
the transformation zone or at the vaginal level. It has previously
been shown that vaccine-induced IgG transudates from the
serum across the endo-cervical and squamo-columnar surfaces
and could therefore play a prominent role in local immunity in
the cervicovaginal mucus [35]. In addition to this local
protective effect, the systemic presence of vaccine-induced
neutralizing antibodies is thought to prevent a new infectious
event (at the same or a distant site) through an exudation process
due to microtrauma by neutralizing viral particles released by
actively infected cells (Figs. 2 and 5). In women infected with
HPV-16 or -18, these neutralizing antibodies may bind to virus
particles and prevent them from progressing to the transformation zone [36].
Serological response in early adolescence
Other studies have shown that immune response to the
vaccine is strongest in early adolescent girls. This is important
since optimal cervical cancer prevention will require prophylactic vaccination against HPV-16 and -18 in early adolescence,
before the onset of sexual activity [52]. In a Phase III clinical trial
(107477/012) involving 773 participants (girls, 10–14 years of
age) the AS04-adjuvanted cervical cancer vaccine was found to
be highly immunogenic with GMTs at Month 7 approximately
twice as high as those observed in young women aged 15–
25 years in the same study [52]. In a separate Phase III study
(104896/013), 626 girls aged 10–14 years received three doses
of AS04-adjuvanted cervical cancer vaccine. Eighteen months
after the first vaccine dose, GMTs for antibodies to HPV-16 and
-18 were at least 5-fold higher than those observed in female
vaccinees aged 15–25 years [46,47,68]. Thus, AS04-adjuvanted
cervical cancer vaccination in pre-teen/adolescent girls achieves
substantially greater antibody responses than those elicited in
young women aged 15–25 years, for whom sustained and longterm protection against incident and persistent HPV-16/18
infection and associated cervical precancerous lesions has
been established [63,69]. The higher antibody titers observed
in 10–14-year-old vaccinees are likely to result in longer
antibody persistence [52] and long-term protection [68].
Serological response in mature women
Epidemiological studies have shown that incident infection
with oncogenic HPV is estimated to occur in 5–10% of women
aged 25–55 years [70–72], and although the frequency of new
HPV infections decreases with age, women in this age range may
remain at risk. In addition, when considering prevalent oncogenic
HPV infections the risk of persistence increases in older women
[73]. The AS04-adjuvanted cervical cancer vaccine has demonstrated long-term immunogenicity for up to 18 months after the
first dose in women over 25 years of age [74]. This Phase III trial
(105879/014) was stratified according to age. One hundred
percent of women seroconverted after vaccination, with an agedependent decrease in antibody response that can be attributed to
age-related decline in immune function [74]. However, even in
the oldest age group, GMTs remained at least 8-fold higher than
those observed following natural infection in another study
(580299/008) [51] and were in the same range as reported in
young women aged 15–25 years, in whom vaccine efficacy has
been demonstrated [46,47]. These data demonstrate that the
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T.F. Schwarz, O. Leo / Gynecologic Oncology 110 (2008) S1–S10
AS04-adjuvanted cervical cancer vaccine is highly immunogenic
in women up to 55 years of age and may offer protection against
new HPV-16/18 infections in a broad age range of women.
[6]
Conclusions
[7]
HPV has learned to evade and down-regulate the host's
innate immune response. Adaptive cell-mediated immunity is
then the primary mechanism of defense, as antibody levels
observed after natural infection seem unreliable for long-term
protection. In order to provide long-term protection against
HPV-16 and -18 infection and associated lesions, prophylactic
cervical cancer vaccination needs to go beyond and improve on
natural immunity.
A cervical cancer vaccine should induce a strong immune
response with high and sustained systemic antibody levels that
highly correlate with high and sustained antibody levels in the
cervix. In contrast to the immune response after natural
infection, the antibody responses in the serum and at the cervix
after vaccination are the key elements of HPV vaccine-induced
responses, together with long-lived plasma cells. The presence
of vaccine-induced neutralizing antibodies at the site of HPV
infection will be key to preventing virus particles from infecting
the transformation zone where cervical cancers usually develop.
The AS04-adjuvanted prophylactic cervical cancer vaccine fits
this immunological profile, eliciting high and sustained antibody responses against both HPV-16 and -18 together with high
and sustained efficacy for up to 6.4 years against HPV-16 and
HPV-18 related infections and precancerous lesions.
[8]
Conflict of interest statement
TFS has received honoraria from GSK as an investigator on HPV vaccine trials,
for lecturing on HPV vaccinology, and as member of HPV advisory boards. OL
is a consultant for GSK but was not involved in the development of HPV
vaccines described in this study.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
Acknowledgments
The authors are thankful to Ulrike Krause, Pascal Cadot, and
Meridian HealthComms Ltd. for their assistance in the
preparation of the manuscript.
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