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Background. In April 2007, Australia became the rst country to introduce a national government-funded
human papillomavirus (HPV) vaccination program. We evaluated the programs impact on genotype-specic
HPV infection prevalence through a repeat survey of women attending clinical services.
Methods. HPV genoprevalence in women aged 1824 years attending family planning clinics in the prevaccine period (20052007) was compared with prevalence among women of the same age group in the postvaccine
period (20102011). The same recruitment and testing strategies were utilized for both sets of samples, and comparisons were adjusted for potentially confounding variables.
Results. The prevalence of vaccine HPV genotypes (6, 11, 16, and 18) was signicantly lower in the postvaccine sample than in the prevaccine sample (6.7% vs 28.7%; P < .001), with lower prevalence observed in both
vaccinated and unvaccinated women compared with the prevaccine population (5.0% [adjusted odds ratio, 0.11;
95% condence interval, 0.060.21] and 15.8% [adjusted odds ratio, 0.42; 95% condence interval, 0.190.93],
respectively). A slightly lower prevalence of nonvaccine oncogenic HPV genotypes was also found in vaccinated
women (30.8% vs 37.6%; adjusted odds ratio, 0.68; 95% condence interval, 0.460.99).
Conclusions. Four years after the commencement of the Australian HPV vaccination program, a substantial
decrease in vaccine-targeted genotypes is evident and should, in time, translate into reductions in HPV-related lesions.
December 2009, general practitioners and other community providers offered free vaccination to women
aged 26 years. Since 2009, routine HPV vaccination
has continued for girls in the rst year of high school
(age, 1213 years) as part of the National Immunization Schedule. During 20072009, an estimated 83%
of girls aged 1217 received at least 1 dose of HPV
vaccine and 70% completed the 3-dose HPV vaccination course [1]. Among women aged 1826 years, recorded coverage in this period was 55% and 32% for
1-dose and 3-dose coverage, respectively [2]. This was
less than true coverage because notication in this age
group to the national vaccine register was not compulsory, although it did attract a small notication
payment per dose [2]. The Australian HPV
vaccination program has exclusively used the quadrivalent vaccine, which protects against HPV genotypes
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METHODS
Study Design and Participants
Tabrizi et al
The second or postvaccine implementation sample comprised women aged 1824 years who had attended FPCs in
the same cities during the recruitment period 20102011 for
Papanicolaou screening. These women would have been aged
1420 years at the time they were vaccinated, if they participated in the school- or community-based components of the
HPV vaccination program between 2007 and 2009. Any
impact measured in this age group would most closely approximate the benet that might be expected for future cohorts of
adolescents. Based on vaccine registry data, the recorded HPV
vaccine coverage among women aged 1824 years in 2011 was
74% for 1 dose and 55% for 3 doses [1, 2]. Under Australian
guidelines, cervical screening begins at age 18 years or 2 years
after rst intercourse, whichever is later. Therefore, on the
basis of their age, the women in the second sample were in
both the vaccinated cohort and eligible for cervical screening
at the time of recruitment. The recruitment for the postvaccine sample is ongoing, and the current study is based on an
interim data analysis.
Of 2 FPCs in Melbourne, only 1 participated in the prevaccine phase, whereas both joined the postvaccine phase. Participants were recruited from both Perth FPCs in both phases.
The Sydney FPC that had participated in the prevaccine phase
moved premises soon afterward to a nearby site within the
city. Both this site and a second major Sydney FPC participated in the postvaccine phase. All the clinics participating in the
prevaccine and postvaccine phases were located within the
same metropolitan areas.
The procedures to recruit participants were identical for the
prevaccine and postvaccine samples. Clinic staff identied ageeligible women at the time of a consultation that included
routine Papanicolaou testing. Invitation to participate depended on judgment by the clinician that there was sufcient time
to raise the study in the context of the clinical visit. Written,
informed consent was obtained from those who agreed to participate. At the time of the Papanicolaou test, each woman
had a sample of exfoliated cervical cells collected in Preservcyt
(Thin Prep, Cytyc) for HPV DNA testing. Information on
age, current use of hormonal contraception, smoking status,
and postcode of residence was collected. Those enrolled in the
postvaccine group were also asked to provide information relating to HPV vaccination status, sexual and reproductive
history, and knowledge of risk factors for cervical cancer. Approval to conduct the study was obtained from research and
ethics committees at each of the sites that enrolled
participants.
Laboratory Testing
16 and 18 [3], the main causes of high-grade cervical intraepithelial neoplasia (CIN grades 2 and 3) in Australian women,
and genotypes 6 and 11, which cause most genital warts [4, 5].
Denitive proof of the programs effectiveness in reducing
cervical cancer will not be evident for several decades.
However, there have already been early signs of success, manifested as substantially lower numbers of both new genital
warts presentations at sexual health clinics [6, 7] and histologically conrmed diagnoses of high-grade cervical lesions [8]
among young women in the vaccine cohort, compared with
their predecessors at the same age.
Another outcome measure that is increasingly being recognized as relevant for HPV vaccine evaluation is the prevalence
of infection with vaccine-targeted genotypes. With placebocontrolled trials no longer ethically feasible, genotype prevalence has been endorsed as an appropriate surrogate outcome
for comparative trials of new HPV vaccine constructs [9], as
well as providing an important basis for population monitoring of vaccine program effectiveness [1012].
We conducted Australias rst study of HPV genoprevalence, known as WHINURS (Women, Human papillomavirus
prevalence, Indigenous, Non-Indigenous, Urban, Rural Study),
just prior to the implementation of the national HPV vaccination program. This study involved recruitment of women at
34 sentinel clinical sites from around the country and provided estimates of the prevalence of specic genital HPV genotypes [13]. With 4 years having elapsed since implementation
of the vaccination program, we initiated a follow-up survey to
assess changes in the prevalence of HPV genotypes in young
Australian women. Here we report on the rst analysis of ndings in women aged 1824 years at participating clinics in 3 of
Australias major cities.
Statistical Analysis
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DNA extraction using the automated MagNA Pure LC isolation and purication system (Roche Molecular Systems) with
the DNA-I isolation kit [14]. Following nucleic acid isolation,
all samples were initially assessed for the presence of 13 highrisk HPV (HR-HPV) genotypes using the Amplicor HPV test
kit (Roche Molecular Systems). Any specimen shown to be
negative for HR-HPV types was tested for the presence of
mucosal HPV DNA using L1 consensus primer set PGMY09PGMY11 [15]. Polymerase chain reaction (PCR) products
were detected by enzyme-linked immunosorbent assay
(ELISA) using a generic biotin-labeled probe for detection of
the presence of mucosal HPV sequences in the sample [16].
Samples positive for HPV by either the Amplicor test or the
PGMY09-PGMY11 PCR-ELISA were subsequently genotyped
using the Linear Array HPV genotyping test (Roche) modied
by using an automated blot processor, BeeBlot (Bee Robotics),
for the hybridization and washing steps, as previously validated by our laboratory [1719]. HPV genotyping proles were
manually interpreted and veried using the HPV reference
guide provided with each test kit. Any sample positive for the
HPV 52/33/35/58 probe line on the Linear Array test was
further tested to conrm the presence or absence of HPV
type 52 [20].
Table 1.
Characteristic
Prevaccine
Group
(n = 202)
Postvaccine
Group
(n = 404)
21.6 (1.8)
21.2 (1.8)
Pa
Postvaccine
Unvaccinated
Group (n = 57)
Postvaccine
Vaccinated
Group (n = 338)
Pb
.005c
21.8 (1.9)
21.1 (1.8)
.001c
.1
.4
192 (95.1)
159 (78.7)
362 (90.9)
312 (78.0)
.08
.8
49 (87.5)
40 (71.4)
304 (91.3)
266 (79.4)
123 (60.9)
60 (29.7)
299 (74.2)
109 (27.6)
.001c
.6
36 (63.2)
15 (26.8)
257 (76.3)
90 (27.3)
<.001c
.8
Data are no. (%) of women, unless otherwise indicated. Percentages do not include missing values.
a
P value for difference across 3 groups: prevaccine, postvaccine unvaccinated, and postvaccine vaccinated.
P < .05.
consistently had the lowest prevalences of HPV, and the differences were particularly striking for the HPV genotypes
covered by the vaccine, with only 5.0% of vaccinated women
in the postvaccine sample having 1 of these genotypes. We
also found signicant differences between the 3 groups in the
prevalence of HPV types 6, 16, and 18 (Table 2) and no signicant differences for selected other HR-HPV genotypes.
Vaccine effectiveness against vaccine-type HPV infection was
73% (95% condence interval [CI], 48%86%; P < .001).
After adjusting for age and use of hormonal contraceptives,
compared with women in the prevaccine sample, those in the
postvaccine sample who reported being vaccinated were significantly less likely to be positive for any HPV genotype (OR,
0.49; 95% CI, 0.340.71), HR-HPV genotypes (OR, 0.48; 95%
Figure 1. Differences in human papillomavirus (HPV) genoprevalence between prevaccine and postvaccine populations. *P < .05 for difference in
percentages between groups. Abbreviations: CI, condence interval; excl, excluding; HR-HPV, high-risk HPV.
1648
Tabrizi et al
characteristics which differed signicantly were age and hormonal contraceptive use (Table 1); we therefore adjusted for
these when comparing HPV prevalence across these 3 groups.
There were highly signicant differences in crude HPV
prevalence between the prevaccine and postvaccine samples
(Figure 1). The prevalence of any HPV genotype was 59.9% vs
48.0% in the prevaccine and postvaccine groups, respectively
(P = .006). For the vaccine-targeted HPV genotypes, the difference was even greater at 28.7% vs 6.7%, respectively
(P < .001). When the postvaccine sample was stratied according to self-reported vaccination status, there were highly significant differences across the 3 groups in the proportions of
women positive for any type of HPV, HR-HPV types, and
HPV vaccine genotypes (Table 2). Vaccinated women
Table 2.
Prevalence of Human Papillomavirus (HPV) Genotypes According to Study and Vaccination Status
HPV Genotype
Prevaccine
Group
(n = 202)
Postvaccine
Group
(n = 404)
Any
121 (59.9)
194 (48.0)
95 (47.0)
76 (37.6)
138 (34.2)
126 (31.2)
High-risk
High-risk excluding 16 and 18
Vaccine types
Postvaccine
Unvaccinated
Group (n = 57)
Postvaccine
Vaccinated
Group (n = 338)
.006
33 (57.9)
157 (46.5)
.007
.002
.1
24 (42.1)
20 (35.1)
111 (32.8)
104 (30.8)
.004
.3
Pa
Pb
58 (28.7)
27 (6.7)
<.001
9 (15.8)
17 (5.0)
<.001
16
18
43 (21.3)
17 (8.4)
20 (4.9)
9 (2.2)
<.001
<.001
6 (10.5)
5 (8.8)
13 (3.9)
4 (1.2)
<.001
<.001
11 (5.5)
2 (0.5)
<.001
2 (3.5)
0 (0.0)
<.001
3 (1.5)
21 (10.4)
1 (0.3)
37 (9.2)
.08
.6
0 (0.0)
9 (15.8)
1 (0.3)
26 (7.7)
.2
.1
11
31, 33, 35, and 45
Data are no. (%) of women.
a
P value for difference across 3 groups: prevaccine, postvaccine unvaccinated, and postvaccine vaccinated.
DISCUSSION
OR (95% CI)b
1.00
0.54 (0.380.78)
1.00
0.56 (0.390.80)
0.92 (0.501.69)
0.97 (0.521.80)
0.49 (0.340.71)
0.50 (0.340.73)
1.00
1.00
HPV positive
Prevaccine
Postvaccine
Postvaccine, not
vaccinated
Postvaccine,
vaccinated
High-risk HPV types
Prevaccine
Using a repeat cross-sectional design involving sentinel clinical sites, we have shown that a substantial and statistically signicant decrease in the prevalence of vaccine-preventable
HPV genotype infections has occurred following implementation of Australias national HPV vaccination program. The decrease was almost entirely restricted to the HPV genotypes
that the quadrivalent vaccine is designed to prevent, occurred
primarily in women who said that they had received the
vaccine, and could not be explained by other differences in the
characteristics of the women in the samples being compared.
As far as we are aware, this nding is the rst genoprevalencebased evidence of the protective effect of HPV vaccination
outside the setting of a clinical trial.
Our observation follows recent Australian reports of postvaccination decreases in genital warts and high-grade cervical
lesions among young women [6, 8]. It is consistent with the
high levels of vaccine coverage achieved under the Australian
program, combined with the efcacy of the HPV vaccine
observed in the prelicensure trials.
OR (95% CI)a
Postvaccine
Postvaccine, not
vaccinated
Postvaccine,
vaccinated
0.53 (0.370.75)
0.55 (0.380.79)
0.82 (0.451.51)
0.88 (0.481.64)
0.48 (0.330.70)
0.50 (0.340.74)
1.00
0.70 (0.491.01)
0.74 (0.511.07)
0.92 (0.491.71)
0.97 (0.521.84)
Postvaccine,
0.68 (0.460.99)
vaccinated
Vaccine types (6, 11, 16, and 18)
0.71 (0.481.04)
Postvaccine, not
vaccinated
Prevaccine
1.00
1.00
Postvaccine
Postvaccine, not
vaccinated
0.16 (0.090.26)
0.42 (0.190.93)
0.16 (0.090.26)
0.40 (0.180.90)
Postvaccine,
vaccinated
0.11 (0.060.21)
0.11 (0.060.21)
1649
1650
Tabrizi et al
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1651
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