The Impact of Quadrivalent Human Papillomavirus (HPV; Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine on Infection and Disease Due to Oncogenic Nonvaccine HPV Types in Sexually Active Women Aged 16–26 Years
The Impact of Quadrivalent Human Papillomavirus (HPV; Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine on Infection and Disease Due to Oncogenic Nonvaccine HPV Types in Sexually Active Women Aged 16 -26 Years
Cosette M. Wheeler
Susanne K. Kjaer
Darron R. Brown
Laura A. Koutsky
Eng Hseon Tay
Kevin A. Ault
Suzanne M. Garland
Grace W. K. Tang
Daron G. Ferris
F. Xavier Bosch
Elmar A. Joura
Robert J. Kurman
Evan R. Myers
Luisa L. Villa
Frank J. Taddeo
Lisa C. Lupinacci
Katherine E. D. Giacoletti
Teresa M. Hesley
(See the editorial commentary by Herrero and the article by Brown et al., on pages 919 -22 and 926 -35, respectively.) Background. We evaluated the impact of a quadrivalent human papillomavirus (HPV) vaccine on infection and cervical disease related to 10 nonvaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) associated with 20% of cervical cancers. The population evaluated included HPV-naive women and women with preexisting HPV infection and/or HPV-related disease at enrollment. Methods. Phase 3 efficacy studies enrolled 17,622 women aged 16 -26 years. Subjects underwent cervicovaginal sampling and Pap testing on day 1 and then at 6 -12-month intervals for up to 4 years. HPV typing was performed on samples from enrollment and follow-up visits, including samples obtained for diagnosis or treatment of HPV-related disease. All subjects who received 1 dose and returned for follow-up were included. Results. Vaccination reduced the rate of HPV-31/33/45/52/58 infection by 17.7% (95% confidence interval [CI], 5.1% to 28.7%) and of cervical intraepithelial neoplasia (CIN) 1-3 or adenocarcinoma in situ (AIS) by 18.8% (95% CI, 7.4% to 28.9%). Vaccination also reduced the rate of HPV-31/58/59 -related CIN1-3/AIS by 26.0% (95% CI, 6.7% to 41.4%), 28.1% (95% CI, 5.3% to 45.6%), and 37.6% (95% CI, 6.0% to 59.1%), respectively. Although a modest reduction in HPV-31/33/45/52/58 -related CIN2 or worse was observed, the estimated reduction was not statistically significant. Conclusions. These cross-protection results complement the vaccine's prophylactic efficacy against disease associated with HPV-6, -11, -16, and -18. Long-term monitoring of vaccinated populations are needed to fully ascertain the population-based impact and public health significance of these findings. Trial registration. ClinicalTrials.gov identifiers: NCT00092521, NCT00092534, and NCT00092482.
Infection with human papillomaviruses (HPVs) is
common; the approximate lifetime risk of acquiring such an
infection is 50% [
]. Approximately 35– 40 HPV types
(members of the Alphapapillomavirus [or A] genus) are
capable of infecting the genital epithelium, although not
all of these types are oncogenic. Consequences of
exposure to these HPV types can include asymptomatic
infection, genital warts [
], and a variety of premalignant
Financial support: Merck Research Laboratories, a division of Merck & Co. The studies
were designed by the sponsor (Merck & Co.) in collaboration with external investigators and
an external data and safety monitoring board. The sponsor collated the data, monitored the
conduct of the study, performed the statistical analysis, and coordinated the writing of the
manuscript with all authors. The authors were actively involved in the collection, analysis,
or interpretation of the data and in the revising of the manuscript for intellectual content and
approved the final manuscript. Page charges were paid by the sponsor.
a Author affiliations are listed at the end of the text.
Reprints or correspondence: Dr. Cosette M. Wheeler, University of New Mexico,
Dept. of Molecular Genetics and Microbiology and Dept. of Obstetrics and
Gynecology, UNM HOPE Clinic Bldg. 191, 1816 Sigma Chi Rd. NE, Albuquerque,
NM 87131 ().
and malignant lesions of the anogenital epithelium [
including cervical cancer. Importantly, a minority of HPV types
lead to a majority of HPV-related disease; HPV-16 and -18 are
associated with 70% of all invasive cervical cancers , and
HPV-6 and -11 are associated with 90% of all genital warts [
Recently, prophylactic administration of a quadrivalent HPV
(types 6, 11, 16, and 18) vaccine to young women was shown to
be highly effective in preventing cervical, vulvar, and vaginal
intraepithelial lesions and genital warts associated with vaccine
HPV types [
]. The quadrivalent vaccine contains virus-like
particles (VLPs) composed of the L1 capsid proteins of HPV-6,
-11, -16, and -18. These L1 molecules self-associate into empty
viral capsid analogues, which contain no infectious viral DNA
but which presumably mimic wild-type viral capsids from an
immunologic perspective .
It is generally accepted that the efficacy of the quadrivalent
vaccine is mediated by the generation of a humoral immune
response against the L1 protein of vaccine VLPs [
that L1 is a highly conserved protein, antibodies to HPV-16 and
-18 VLPs generated by the immune system in response to
vaccination may be able to neutralize virions of related HPV types,
effectively preventing infection and subsequent disease
associated with these types (cross-protection). Although neutralizing
antibodies generated in response to vaccination are
conformationally dependent and type specific , there are HPV types
that share neutralizing epitopes, and therefore it is possible that
1 neutralizing antibody will be able to neutralize virions from 1
high-risk type [
]. Additionally, the humoral immune
response to foreign protein antigens results in many different
antibody molecules generated from various fragments of the
L1 protein after degradation and presentation by
antigenpresenting cells. Therefore, VLPs likely induce the production of
a plethora of antibody molecules, some of which may have the
potential to cross-protect.
Established high-risk HPV types within the
Alphapapillomavirus genus include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59
]. All of these HPV types, with the exception of 51 and 56, are
classified in either the A9 or A7 species. As such, the L1 proteins
of HPV-16 and -18 share varying degrees of homology with
respective A9 species members (types 31, 33, 35, 52, and 58) and
A7 species members (types 39, 45, and 59). These nonvaccine A9
and A7 species are responsible for up to 20% of all cervical
]. Cross-protection against these nonvaccine high-risk
HPV types could potentially increase the quadrivalent vaccine’s
impact on cervical cancer risk. Given that there is currently no
established standardized definition for cross-protection, the
World Health Organization Expert Committee on Biological
Standardization recommends that demonstration of
crossprotection be established by observed reductions in the
incidence of cervical intraepithelial neoplasia (CIN) of any grade
(abbreviated here as CIN1–3/adenocarcinoma in situ [AIS]),
CIN2–3 or AIS (abbreviated here as CIN2–3/AIS), and/or viral
persistence due to nonvaccine HPV types.
For women not previously exposed to HPV-16 or -18
(perprotocol population), the quadrivalent HPV vaccine has been
shown to prevent 99% of CIN2–3/AIS cases related to HPV-16
and -18 [
]. In an intention-to-treat (ITT) population that
included both women who were HPV-16 and -18 naive and those
who were HPV-16 and -18 infected, the vaccine was 44%
effective against incident CIN2–3/AIS related to HPV-16 or -18 (all
but 1 case in vaccinees occurred in subjects with HPV-16/18
infection before vaccination) [
]. The prospective data reported
here address the quadrivalent vaccine’s efficacy against infection
and disease with nonvaccine HPV types in an ITT population
that included both HPV-naive women and women with
preexisting HPV infection and/or HPV-related disease at enrollment.
HPV types analyzed include those whose L1 proteins share
80% amino acid homology with either HPV-16 or -18 and are
individually responsible for 2% of cervical cancers (31, 33, 45,
52, and 58). The impact of the vaccine on other high-risk HPV
types (35, 39, 51, 56, and 59) is also presented.
Study objectives. The primary prespecified objective of the
present analysis was to determine whether administration of
quadrivalent HPV vaccine reduces the incidence of infection of
6 months’ duration or cervical disease (definitions are
provided below) associated with HPV-31 and -45 (originally
identified as the 2 most common HPV types associated with cervical
cancer worldwide after HPV-16 and -18 [
]) and with HPV-31,
-33, -45, -52, and -58 (the 5 most common HPV types associated
with cervical cancer worldwide after HPV-16 and -18 [
]) in an
ITT population. Other end points included the incidence of
infection of 6 months’ duration or disease associated with
nonvaccine A9 species members (31, 33, 35, 52, and 58), nonvaccine
A7 species members (39, 45, and 59), and all tested nonvaccine
HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, and 59).
Data sources. Data for the analysis of disease end points was
derived from the combined database of 2 pivotal phase 3
randomized controlled trials of the quadrivalent HPV (type 6, 11,
16, and 18) vaccine (Merck & Co.) known as FUTURE I and
FUTURE II (protocol 013 [NCT00092521] and protocol 015
[NCT00092534], respectively). Data for the analysis of infection
end points was derived from protocol 012 (NCT00092482), a
substudy of protocol 013. Protocol 012 was a phase 3,
randomized, double-blind, placebo-controlled immunobridging study.
The design of these trials has been described elsewhere [
Description of primary analyses for protocols 012 and 013/015
can be found in the companion article by Brown et al. .
End-point definitions. All end-point definitions were
prespecified. Infection was defined as detection of the same HPV
type in cervicovaginal/anogenital swab samples at 2
consecutive visits spaced 6 months apart ( 1-month visit windows) or
as the presence of cervical/genital disease associated with the
relevant type (with type-specific HPV DNA detected in
cervicovaginal or anogenital swab samples at the visit directly before or
after biopsy). Data validating the use of the 6-month-infection
end point are included in the online-only appendix in Brown et
]. Disease was defined as diagnosis in a tissue sample of a
composite end point of CIN1–3, AIS, or cervical cancer by a
4-member pathology panel with type-specific HPV DNA
detected in tissue from the same lesion, as described elsewhere
Clinical follow-up and laboratory testing. Colposcopists
were trained to locate and biopsy all discrete cervical
abnormalities. Biopsy samples were processed, and adjacent histological
sections of each sample were first read for clinical management
by pathologists at a central laboratory (Diagnostic Clinical
Laboratories) who were unaware of treatment-group assignments
and HPV status. Biopsy samples were fixed in formalin, and all
investigators were instructed to ship on the same day that
specimens were collected. Samples were processed within 24 h to
insure that nucleic acids were not compromised. All polymerase
chain reaction (PCR) targets were 300 bp [
]. The stability
of amplification products of this size from formalin-fixed,
paraffin-embedded tissue blocks has been demonstrated [
Statistical analyses. These analyses were conducted in all
subjects who received 1 injection of quadrivalent HPV vaccine
or placebo and returned for follow-up, regardless of the presence
of HPV infection or HPV-related disease at enrollment.
Follow-up for end-point ascertainment started after day 1.
Analysis plans were developed prospectively. To address the
primary hypotheses with respect to infection or disease end
points, a 1-sided test ( 0.025) of the null hypothesis that the
vaccine efficacy (VE; defined as 100[1 relative risk]) is 0%
was conducted. The alternative hypothesis stated that the VE is
0%. A point estimate of the VE and the corresponding 2-sided
95% confidence interval (CI) were provided. Rejection of the
null hypothesis (i.e., the statistical criterion for success)
corresponds to a lower bound of the CI that exceeds 0%. We used an
exact analysis that accounted for the amount of follow-up (i.e.,
person-time at risk) in the vaccine and placebo arms.
Protocols 013 (including the 012 substudy) and 015 enrolled
17,622 subjects combined (8810 vaccine and 8812 placebo). Of
these subjects, 17,599 (99.9%) received 1 dose of vaccine or
placebo. The median SE age of subjects was 20.0 2.1 years,
and the range was 15–26 years. Subjects had a median lifetime
number of sex partners of 2. Detailed demographics for subjects
enrolled in protocols 013 and 015 have been described elsewhere
]. At study end, 85.4%, 87.5%, and 93.6% of subjects in
protocols 012, 013, and 015 had completed all scheduled visits in
the efficacy follow-up period.
Subjects were included in the analyses presented in this article
regardless of the presence of HPV infection or HPV-related
disease at enrollment. On day 1, 4.6%, 5.9%, and 0.9% of subjects
had cytological evidence of atypical squamous cells of
undetermined significance, low-grade squamous intraepithelial lesions,
and high-grade squamous intraepithelial lesions, respectively.
Of these subjects with a Pap abnormality on day 1, 56.0%,
87.2%, and 93.1% were positive to 1 or more of the 14 tested
HPV types, respectively. The majority of CIN2–3/AIS lesions
observed in the placebo arm were associated with HPV-16
–related HPV types (A9 species). Of these CIN2–3/AIS lesions,
29.5% were associated with HPV-31, -33, -35, -52, and/or -58
with no coinfection with vaccine HPV types, and 13.7% were
associated with HPV-31, -33, -35, -52, and/or -58 with
coinfection with vaccine HPV types. In the vaccine arm, lesions
associated with a mix of vaccine and nonvaccine HPV types were rare,
due to high VE for HPV-6, -11, -16, and -18.
In the combined population of protocols 013 and 015, a total
of 32.8% of enrolled subjects were DNA positive to 1 of 14
HPV types tested on day 1 (table 1). HPV-16 was the most
common HPV type, followed by 56, 51, and 52 (table 1).
Subjects were followed for an average of 3.6 years after receipt
of dose 1. A total of 3459 subjects (1732 in the vaccine arm and
1727 in the placebo arm) were included in the ITT analysis of
infection from protocol 012. This population included both
HPV-naive women and women with preexisting HPV infection
and HPV-related disease at enrollment. Administration of
quadrivalent HPV vaccine reduced the combined incidence of
infection (table 2) with HPV-31/45 by 31.6% (95% CI, 15.4% to
44.7%) and with HPV-31/33/45/52/58 by 17.7% (95% CI, 5.1%
to 28.7%). To address any potential ascertainment bias resulting
from the higher frequency of colposcopy, biopsy, and definitive
therapy among placebo recipients or from the inclusion of
cervical biopsy samples in the analysis of infection (see Methods),
we did supportive analyses whereby infection was restricted to
detection of HPV DNA in cervicovaginal/anogenital swab
samples only. In these analyses, the efficacy for HPV-31/33/45/52/58
infection was 16.9% (95% CI, 3.9% to 28.2%). Individual HPV
types with statistically significant reductions in infection for the
vaccine arm compared with the placebo arm included HPV-31
(33.6% [95% CI, 14.6% to 48.5%]) and HPV-59 (24.6% [95%
CI, 1.9% to 42.2%]). Additional analyses of efficacy against
infection of 6 months’ duration were also conducted. The
definition of infection was limited to detection of HPV DNA in
cervicovaginal swab samples (primary analyses of infection
included biopsy PCR data). Data from the swab-only infection
analyses were consistent with the reported results, because the
majority of cases of infection of 6 months’ duration were based
solely on the detection of HPV in swab samples. For example,
efficacy against infection with HPV-31/33/45/52/58 of 6
NOTE. Data are no. (%) of subjects. The percentage of subjects with day
1 results for 1 HPV type is calculated as 100 (no. with results/total no. in
study arm). The percentages of subjects with specified categories of day 1
PCR positivity are calculated on the basis of the no. of subjects with a
nonmissing day 1 PCR result for 1 of the 14 tested HPV types.
a Negative for the respective HPV type(s) on day 1 for all required swab
samples and (if obtained) biopsy samples.
b Positive for 1 of the listed HPV type(s) on day 1 for 1 required swab
sample or (if obtained) biopsy sample.
c Incomplete data to determine whether a subject was negative for all 14
months’ duration determined using swab data only was 16.9%
(95% CI, 3.9% to 28.2%), compared with the 17.7% (95% CI,
5.1% to 28.7%) reported above (cases were counted after day 30
in the swab-only analysis).
A total of 17,160 subjects (8562 in the vaccine arm and 8598 in
the placebo arm) were included in the analysis of disease from
protocols 013 and 015 (tables 3 and 4). Administration of
quadrivalent HPV vaccine reduced the incidence of
HPV-31/45–related CIN1–3/AIS by 22.2% (95% CI, 4.4% to 36.7%) (table 3).
Efficacy against HPV-31/45– and HPV-31/33/45/52/58 –related
CIN1 was 24.6% (95% CI, 4.1% to 40.8%) and 23.5% (95% CI,
10.8% to 34.4%), respectively. Efficacy against the combined
incidence of HPV-31/33/45/52/58 –related CIN1–3/AIS was
18.8% (95% CI, 7.4% to 28.9%). Although a modest reduction
in HPV-31/33/45/52/58 –related CIN2 or worse was observed,
the estimated reduction was not statistically significant.
Combined efficacy against CIN1–3/AIS related to the 10
tested nonvaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58,
and 59) collectively was 15.1% (95% CI, 6.0% to 23.4%) (table
4). Efficacy against CIN2 or worse related to these 10 types
combined was 13.2% (95% CI, 2.0% to 26.0%) (data not shown).
VE against the combined incidence of CIN1–3/AIS related to
nonvaccine A9 species HPV type (31, 33, 35, 52, and 58) and
nonvaccine A7 species HPV types (39, 45, and 59) was 19.2%
(95% CI, 7.9% to 29.1%) and 14.7% (95% CI, 4.4% to 30.4%),
respectively. Individual HPV types with significant observed
efficacy against CIN1–3/AIS included HPV-31 (26.0% [95% CI,
6.7% to 41.4%]), HPV-58 (28.1% [95% CI, 5.3% to 45.6%]),
and HPV-59 (37.6% [95% CI, 6.0% to 59.1%]). Other HPV
types displayed positive effects, but differences were not
The contribution of HPV-31 cross-protection to composite
HPV type cross-protection (i.e., against all tested nonvaccine
HPV types and against the 2 other nonvaccine type composite
groupings [HPV-31/33/35/52/58 and HPV-31/33/45/52/58]) is
shown in table 5. Significant efficacy against CIN1–3/AIS was
observed for each of the 3 nonvaccine HPV type composites
when HPV-31 was removed.
We conducted an ITT analysis and estimated the
crossprotective vaccine impact for 10 nonvaccine HPV types (31, 33,
35, 39, 45, 51, 52, 56, 58, and 59) in phase 3 efficacy studies of the
quadrivalent HPV vaccine. The analysis of cross-protective
efficacy against cervical disease included all women in the FUTURE
I and FUTURE II trials who received 1 dose of vaccine or
placebo. The analysis of cross-protective efficacy against infection
included all women entering protocol 012 (a substudy of
protocol 013 [FUTURE I]) who received 1 dose of vaccine or
placebo. It should be noted that, as a result of the high efficacy of the
vaccine seen in FUTURE I and II, the independent data and
safety monitoring board for these studies recommended ending
follow-up early. The placebo arm was offered the potential
benefits of vaccination as quickly as possible.
Our results demonstrate statistically significant cross-protective
reductions in infection and composite CIN (mostly due to
reductions in CIN1) end points among a population consisting of
both HPV-naive women and women with preexisting HPV
infection and HPV-related disease at enrollment. Although a
modest reduction in HPV-31/33/45/52/58 –related CIN2 or worse
was observed, the estimated reduction was not statistically
significant. Previous investigations of HPV vaccine
crossprotection did not report disease end points or ITT analyses,
which are critical to estimating the potential public health
benefits of cross-protection [
Within specific geographic regions, baseline prevalence and
therefore cumulative HPV exposure will naturally vary among
6 months’ duration in the
populations. This variance will be related to both sexual
behaviors and to the individual HPV genotypes initially established,
given unique population genetics and exposure frequencies (i.e.,
founder effects) [
4, 25, 26
]. A significant proportion (32.8%) of
the FUTURE I and II trial participants were infected at the time
of study enrollment with 1 or more of the genital HPV types
under evaluation for vaccine cross-protection. Despite prevalent
oncogenic HPV infections with both vaccine and nonvaccine
HPV types, cross-protective VE against infection was observed
for both composite end points as well as the individual HPV
types 31 and 59. A corresponding reduction in disease,
principally attributable to reductions in CIN1, was observed for the
HPV-31 or -45
CIN2 or worse
HPV-31, -33, -45, -52, or -58
CIN2 or worse
NOTE. Disease was defined as diagnosis in a tissue sample of a composite end point of CIN1–3, AIS, or cervical cancer by a 4-member pathology panel with
type-specific HPV DNA detected in tissue from the same lesion. A subject is counted only once within each applicable row. The ITT population was composed
of all subjects who received 1 injection of quadrivalent HPV vaccine or placebo and returned for follow-up, regardless of the presence of HPV infection or
HPV-related disease at enrollment. Follow-up for end-point ascertainment started after day 1. CI, confidence interval; PYR, person-years at risk.
a No. of subjects who received 1 dose of vaccine or placebo and returned for least 1 follow-up visit.
b Cases per 100 PYR.
composite end point of HPV-31/33/45/52/58 –related disease. A
statistically significant reduction in disease due to specific
individual HPV types was also observed for HPV-31/58/59.
The interpretation of this study is accompanied by some
limitations. Although cross-protective efficacy was detected
through 3.6 years in this study, uncertainties remain regarding
the durability of HPV vaccine immunity. It is possible that
differences in cross-protective immunity against nonvaccine HPV
types and type-specific immunity against vaccine HPV types
may emerge if overall vaccine immunity wanes. In addition, our
study was not powered to measure reductions in CIN2–3 due to
nonvaccine HPV types in the ITT population, and a significant
number of CIN2–3 end points included coinfections with HPV
vaccine types (i.e., 16 and 18). Additionally, assessment of
disease end points may have been confounded by reductions in
colposcopic biopsy due to reductions in referrals for disease
related to HPV-6/11/16/18 infection in the vaccine arm. However,
assessment of HPV vaccine cross-protection for HPV infections
(via swab samples only) was not affected by ascertainment bias,
because samples were collected for both vaccine and placebo
recipients at each indicated study visit (efficacy against infection
with HPV-31/33/45/52/58 as determined using swab samples
only was 16.9% [95% CI, 3.9% to 28.2%]). Despite these
limitations, the reductions in type-specific infections mirror the
reductions in CIN1 and provide evidence of a partial
crossprotective benefit for the quadrivalent HPV vaccine.
Because coinfection with genital HPVs is common, the benefit
of any cross-protection against nonvaccine oncogenic HPV
types will not be fully additive. This is highlighted by analyzing
data from the placebo arm. In the placebo arm, there were
273 cases of CIN2–3/AIS containing HPV-16/18 DNA and 246
containing HPV-31/33/52/58 DNA. If the benefit of
crossprotection were fully additive, we would expect 519 cases (273
plus 246) of HPV-16/18/31/33/52/58 –related CIN2–3/AIS.
However, because cross-protective efficacy is not fully additive,
there were actually 436 cases of CIN2–3/AIS containing
HPV16/18/31/33/52/58 DNA. This indicates that roughly 19% (83/
436) of cases of CIN2 or worse containing HPV-16/18/31/33/
52/58 DNA were coinfected.
The potential benefit of cross-protection is relevant to 2
separate disease risk compartments. First, in women who become
infected with nonvaccine types in the absence of HPV-6/11/
16/18 infection, disease reductions due to cross-protective
effects of the quadrivalent vaccine on CIN of any grade might
provide an incremental benefit by reducing referrals for repeat
Pap testing, colposcopic procedures, or treatment. Second, an
additional benefit of the quadrivalent HPV vaccine may also be
provided to women at risk for coinfection with both vaccine and
nonvaccine HPV types.
Because overall and type-specific reductions in HPV-related
disease will be evaluated over time, the current study presents an
opportunity to discuss the potential relevance of existing
competing disease risks, including potential niche replacement and
unmasking, as observed in other vaccine settings [
Unmasking of disease risk refers to when coinfections of related
etiological agents are initially unassigned due to sampling or
detection bias. Unmasking due to nonvaccine HPV type–specific
coinfections represents a potentially predictable competing
disease risk, at least in a subset of at-risk women [
some women with partners who are infected with both vaccine
and nonvaccine HPV types, protection against vaccine HPV
types may unmask risks associated with infection by nonvaccine
oncogenic HPV type(s), and these infections may result in
CIN2–3/AIS (or cancer). An intervention that reduces the risk of
acquisition of infection with nonvaccine HPV types among
vaccinated subjects will reduce this unmasking phenomenon—
thereby further reducing the vaccinated subject’s overall risk of
The term “niche replacement” has been used to reflect the
emergence of unanticipated disease risks. Changes in a biological
niche can presumably alter competitive interactions among
disease-related agents or can result in the emergence of more
virulent or pathogenic “strains.” Niche replacement has been
causally associated with some vaccines, such as 7-valent
pneumococcal conjugate vaccine [
]. In contrast to unmasking of
disease risks, niche replacement due to alterations in the overall
fitness or carcinogenicity of nonvaccine HPV types is not
supported by evolutionary data, although this presumption must be
borne out through long-term follow-up. Bacterial agents with
large genomes and viruses with high mutation rates can readily
drive genetic adaptations; however, HPVs demonstrate little to
no capacity for mutation (i.e., as few as 1 mutation or
singlenucleotide substitution in 300 bp over several thousands of
Anticipating niche replacement due to competitive
interactions among HPV genotypes is a potentially more difficult task,
given that natural history studies of type-specific HPV infections
have presented conflicting observations. For instance, incident
HPV infection after an HPV-16 infection, type-specific HPV
persistence/clearance, and coinfection have in some studies
demonstrated near independence [
]. Examples of
contrasting observations include (1) a decreasing trend in the risk
estimates for CIN2 or worse among women infected with HPV-16
and either 0, 1, or multiple noncarcinogenic HPV types [
antagonism between the noncarcinogenic HPV types 6 or 11 and
HPV-16 resulting in a reduced risk for both CIN and invasive
cervical cancer [
]; and (3) increased odds of acquiring a
subsequent HPV-58 infection after an incident HPV-16 or -18
infection compared with individuals not infected with HPV-16
or -18 . The potential for disease replacement driven by
illdefined existing or emerging competitive interactions among
HPV genotypes after HPV vaccination remains to be
In long-term postmarketing surveillance programs,
consideration of the above issues will be important to properly
characterize any changes in type-specific HPV prevalence and disease
], particularly among cervical precancers (i.e.,
CIN2–3). Baseline and longitudinal measurements that
compare type-specific HPV prevalence observed in women
diagnosed with CIN1–3 with that observed among women with
asymptomatic HPV infections (i.e., normal cytology) will be
required to distinguish potential HPV type replacement from
expected unmasking of competing disease risks. It will also be
important for long-term evaluations of HPV vaccines to be
conducted in true population-based settings and to account for
any complementary modifications implemented within cervical
screening programs. Even with highly effective interventions,
the potential for overestimation of effects exists if replacement
or unmasking is observed.
In summary, administration of quadrivalent HPV vaccine to a
partially infected population reduced the incidence of infection
of 6 months’ duration and CIN1 associated with additional
nonvaccine oncogenic HPV types. Although a modest reduction
in HPV-31/33/45/52/58 –related CIN2 or worse was observed,
the estimated reduction was not statistically significant. These
results complement the vaccine’s high prophylactic efficacy
against disease associated with HPV-6/11/16/18 infection.
Longterm monitoring of vaccinated populations will be needed to
more fully ascertain the population-based impact and public
health significance of these findings. Looking toward the future,
second-generation HPV vaccines targeting a broader spectrum
of oncogenic HPV types may become available within the next
decade, expanding the benefits of HPV prophylactic vaccines
beyond the current specific and cross-protective vaccine
Author affiliations. Department of Molecular Genetics and
Microbiology and Department of Obstetrics and Gynecology,
University of New Mexico, Albuquerque NM (C.M.W.); Department
of Virus, Hormones, and Cancer, Institute of Cancer Epidemiology,
Danish Cancer Society/Rigshospitalet, Copenhagen, Denmark
(S.K.K.); National Cancer Detection Clinic, Reykjavik, Iceland
(K.S.); Department of Clinical Medicine, University of Bergen and
Department of Obstetrics and Gynecology, Haukeland University
Hospital, Bergen, Norway (O.-E.I.); Institute of Public Health,
Cuernavaca, Morelos, Mexico (M.H.-A.); National Research
Center, Group Saludcoop, Bogotá, Colombia (G.P.); Department
of Medicine, Indiana University School of Medicine, Indianapolis
(D.R.B.); Department of Epidemiology, University of Washington,
Seattle (L.A.K.); KK Women’s and Children’s Hospital, Singapore
(E.H.T.); Epidemiology HIV and STD Unit, Universidad Peruana
Cayetano Heredia, Lima, Peru (P.G.); Department of Gynecology
and Obstetrics, Emory University School of Medicine, Atlanta,
Gerogia (K.A.A.); Microbiology and Infectious Diseases
Department, Royal Women’s Hospital and Department of Obstetrics and
Gynecology, University of Melbourne, Melbourne, Victoria,
Australia (S.M.G.); Department of Gynecology and Obstetrics, Medical
University of Vienna, Vienna, Austria (S.L. and E.A.J.); Karolinska
Institute at Danderyd Hospital, Stockholm, Sweden (S.-E.O.);
Department of Obstetrics and Gynecology, University of Hong Kong,
Hong Kong Special Administrative Region, China (G.W.K.T.);
Department of Family Medicine and Obstetrics and Gynecology,
Medical College of Georgia, Augusta, Georgia (D.G.F.);
Department of Obstetrics and Gynecology, University Central Hospital,
Helsinki, Finland (J.P.); Direction Risques Biologiques,
Environnementaux et Occupationnels, Institut National de Santé Publique du
Québec, Montréal, Canada (M.S.); Institut Catala d’Oncologia,
IDIBELL, Barcelona, Spain (F.X.B.); Department of Medical
Microbiology, Lund University, Lund, Sweden (J.D.); Departments of
Gynecology and Obstetrics, Pathology, and Oncology, Johns
Hopkins University School of Medicine, Baltimore, Maryland (R.J.K.);
Department of Dermatology and Venereology, Center of
Diagnostics and Treatment of Sexually Transmitted Diseases, Warsaw
Medical University, Warsaw, Poland (S.M.); National Institute of
Cancer, Bogotá, Colombia (N.M.); Department of Obstetrics and
Gynecology, Duke University Medical Center, Durham, North
Carolina (E.R.M.); Department of Virology, Ludwig Institute for
Cancer Research, Sao Paulo, Brazil (L.L.V.); Merck Research
Laboratories, West Point, Pennsylvania (F.J.T., J.B., C.R., A.T., L.C.L.,
K.E.D.G., M.J., S.V., T.M.H., and E.B.).
Potential conflicts of interest. N.M. has received lecture
fees, advisory board fees, and consultancy fees from Merck and
Sanofi Pasteur MSD. S.-E.O. has received lecture fees from
Merck. M.H.-A. has received lecture fees and grant support from
Merck. O.-E.I. has received lecture fees from Merck and
GlaxoSmithKline (GSK). C.M.W. has received funding through her
institution to conduct HPV vaccine studies for GSK. K.A.A. has
received consultancy and advisory board fees from Merck and
has received funding through his institution to conduct HPV
vaccine studies for Merck and GSK and nonvaccine clinical trials
for Gen-Probe. F.X.B. has received lecture fees from Merck and
GSK and has received funding through his institution to conduct
HPV vaccine studies for GSK. J.P. has received consultancy fees,
advisory board fees, and lecture fees from Merck. J.D. has
received consultancy fees, lecture fees, and research grants from
Merck and Sanofi Pasteur MSD. S.L. has received lecture fees
from Merck and Sanofi Pasteur MSD. E.A.J. has received lecture
fees from Merck, Sanofi Pasteur MSD, and GSK. S.K.K. has
received consultancy fees and funding through her institution to
conduct HPV vaccine studies for Sanofi Pasteur MSD and
Digene. S.M.G. has received advisory board fees and grant support
from Commonwealth Serum Laboratories and GSK and lecture
fees from Merck. D.G.F. has received consultancy fees and
funding through his institution to conduct HPV vaccine studies for
GSK and has received lecture fees and consultancy fees from
Merck. K.S. has received consultancy fees from Merck. S.M. has
We thank Shuang Lu and Carolyn Maass for statistical programming
HPV Cross-Protection in Non–HPV-Naive Women ● JID 2009:199 (1 April) ● 943
18.8 (5.5 to 30.3)
19.0 (5.9 to 30.3)
NOTE. Disease was defined as diagnosis in a tissue sample of a composite end point of CIN1–3, AIS, or cervical cancer by a 4-member
pathology panel with type-specific HPV DNA detected in tissue from the same lesion. A subject is counted only once within each applicable row.
The ITT population was composed of all subjects who received 1 injection of quadrivalent HPV vaccine or placebo and returned for follow-up,
regardless of the presence of HPV infection or HPV-related disease at enrollment. Follow-up for end-point ascertainment started after day 1. CI,
confidence interval; PYR, person-years at risk.
a No. of evaluable subjects (i.e., no. of subjects in the given population who also had
b Cases per 100 PYR.
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HPV- 33 /45/52/58 related HPV- 33 /35/52/58 related HPV- 33 /35/39/45/51/52/56/58/59 related HPV- 33 /45/52/58 related HPV- 33 /35/52/58 related HPV- 33 /35/39/45/51/52/56/58/59 related 1.1 1.1 2.1 0.6 0.6 0.8 384 395 737 192 203 289 29,476.8 29,488.5 29,152.0 29,688.1 29,684.1 29,663.0 1.3 1.3 2.5 0.6 0.7 1 . 0 1 follow-up visit).