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Immunogenicity of Quadrivalent HPV Vaccine Among Girls 11 to 13 Years of

Age Vaccinated Using Alternative Dosing Schedules: Results 29 to 32 Months
After Third Dose

Article  in  The Journal of Infectious Diseases · July 2013

DOI: 10.1093/infdis/jit363 · Source: PubMed

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 MAJOR ARTICLE

Immunogenicity of Quadrivalent HPV Vaccine

Among Girls 11 to 13 Years of Age Vaccinated
Using Alternative Dosing Schedules: Results 29
to 32 Months After Third Dose
D. Scott LaMontagne,1,2 Vu Dinh Thiem,3 Vu Minh Huong,1,2 Yuxiao Tang,1,2 and Kathleen M. Neuzil1,2
1
PATH, Seattle, Washington and 2Hanoi, Vietnam, 3National Institute of Hygiene and Epidemiology, Hanoi, Vietnam

Background. Immune response to quadrivalent human papillomavirus (HPV) vaccine delivered at 0, 2, and 6
months in young adolescent females plateaus around 24 months after immunization. Antibody levels >24 months

Downloaded from http://jid.oxfordjournals.org/ by guest on February 2, 2016

postvaccination using extended dosing schedules is unknown.
Methods. We conducted a follow-up immunogenicity study of adolescent girls in Vietnam who participated in
a noninferiority trial to investigate whether immune responses using 3 alternative dosing schedules (0, 3, 9 months;
0, 6, 12 months; or 0, 12, 24 months) are noninferior to the standard schedule at >2 years after immunization.
Results. Quadrivalent HPV vaccine immunogenicity delivered on 3 alternative dosing schedules was noninfe-
rior for types 6, 11, 16, and 18 at 32 months post-dose 3 compared to the standard schedule. Pre-dose 3 antibody
levels for the 0, 12, 24 month schedule were similar to those measured 32-months post-dose 3.
Conclusions. We found similar antibody concentrations ≥29 months after 3 doses of HPV vaccine regardless of
dose-timing, and extended schedules do not produce inferior immune responses. Our findings also suggested that 2
doses of HPV vaccine delivered at 0 and 12 months might afford similar protection. Evidence supporting dosing
flexibility could be important for national HPV vaccination policies.
Keywords. human papillomavirus; HPV vaccine; immunogenicity; adolescents; vaccination schedule; Vietnam.

BACKGROUND younger populations [3, 5, 8, 9, 11–14]. Vaccine efficacy

Human papillomavirus (HPV) vaccines have elicited
strong and sustained immune responses in both adult
women followed for vaccine efficacy [1–7] and adoles-
cent populations included in immune-bridging studies
[8–10]. The 3-dose schedule (0, 2, and 6 months)
induced high strain-specific antibody concentrations
1 month post-dose 3, and this response plateaued
24 months (after the first dose), with levels higher in
Received 14 February 2013; accepted 7 May 2013; electronically published 30
July 2013.
Preliminary results of this study were presented as an oral poster (CPO7-332) on
Wednesday, 5 December 2012 at the 28th International Papillomavirus Conference,
San Juan, Puerto Rico.
Correspondence: D. Scott LaMontagne, PhD, MPH, FRSPH, PATH, 2201 Westlake
Ave, Ste 200, Seattle, WA 98121(slamontagne@path.org).
The Journal of Infectious Diseases 2013;208:1325–34
© The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/infdis/jit363
at least 8 years postimmunization is being maintained
in adult women [3, 7], and recent studies have suggest-
ed that 2 doses are also efficacious [15].
A study among adolescents in Vietnam demonstrat-
ed that the immune response to HPV vaccines deliv-
ered on alternative schedules at 0, 3, 9 months and 0, 6,
12 months was noninferior to that produced when 3
doses were delivered according to the 0, 2, 6 month
standard schedule [16]. This study was the first to our
knowledge to measure immunogenicity of 3 doses de-
livered over a 2-year period. The results for the 0, 12, 24
month schedule were mixed: geometric mean titers
(GMTs) for types 11 and 18 were similar to those
found in the girls on the 0, 2, 6 month schedule, and
GMTs for types 6 and 16 were lower than the standard
schedule [16]. It was unclear whether the lower anti-
body responses seen with the yearly schedule were due
to an age-dependent immune response (because the
girls were older when they received the third dose)

Quadrivalent HPV Vaccine Immunogenicity • JID 2013:208 (15 October) • 1325

[8, 9] or were an artifact of the time of the measurement—
1 month after the third dose of vaccine. When delivered on the
standard schedule, the immune response to HPV vaccine in
young adolescent females plateaus at 18 or 24 months after first
dose [9, 17, 18]. Whether a similar immune response plateau is
generated using alterative or extended schedules is still unknown.
Data from long-term immunogenicity studies in adolescents
could provide early indications on the persistence of antibody
titers, which is critical for understanding long-term duration of
protection and the effects of alternative schedules [19].
To understand the duration of the antibody response of
quadrivalent HPV vaccine generated with alternative vaccina-
tion schedules, we extended our previous study of girls 11–13
years of age in Vietnam[16] to investigate whether anti-HPV
16 and anti-HPV 18 immune responses >24 months post-dose
3 are noninferior using 3 different alternative dosing schedules
(0, 3, 9 months; 0, 6, 12 months; or 0, 12, 24 months) to those
obtained when the vaccine is administered on the standard
3-dose schedule of 0, 2, 6 months.
METHODS
We designed a cross-sectional immunogenicity study of adoles-
cents who received 3 doses of HPV vaccine and collected a
single 7-mL blood sample from girls who completed a previous
open-label, cluster-randomized trial of alternative dosing
schedules (NCT00524745) [16]. Girls on the standard 0, 2, 6
month schedule were followed up for 29 months, and those on
the alternative schedules were followed up for 32 months. An
Figure 1. Study schedule, cluster-randomized trial and follow-up study of alternative dosing schedules, quadrivalent human papillomavirus (HPV)
vaccine, adolescent girls aged 11–13 years, Vietnam.
1326 • JID 2013:208 (15 October) • LaMontagne et al
interim immunogenicity measure at 20 months post-dose 3
was performed for girls on the 0, 12, 24 month alternative
schedule (Figure 1).
Consenting Procedures and Ethics Review
Parents of all girls eligible for this study were contacted by local
study personnel in collaboration with school leaders and teach-
ers at both primary and secondary schools in the study area
of Hoa Binh province, Vietnam. Parents were given written
information on this study—including the purpose, risks, and
benefits—and they were invited to attend a study information
meeting. Local study staff was available to answer parental
questions. Parents could consent at the time of approach, or
they could return the signed consent form with their daughter
up to the date of the scheduled blood draw. Written assent was
also obtained from the girl, either at the time of parental
consent or at the scheduled date of the blood draw. All consents
were additionally verified by study staff, and assent by the girl
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was reaffirmed at the time of the blood draw.
This follow-up study and its procedures were approved by
institutional review boards in Vietnam (Ministry of Health and
National Institute of Hygiene and Epidemiology) and the
United States (Western Institutional Review Board).
Specimen Collection, Handling, and Analysis
All procedures for the collection, handling, storage, and trans-
port of blood/serum samples were completed in accordance
with the same procedures of the original trial [16]. Blood speci-
mens were collected and centrifuged in the field and stored on
dry ice for transport to the central laboratory at the National
Institute of Hygiene and Epidemiology in Hanoi, Vietnam.
Two air shipments of samples were sent to Merck Research
Laboratories (United States) in August 2011 and August 2012.
The same type-specific competitive Luminex immunoassay was
used by Merck (United States) to quantify levels of neutralizing
antibodies for all 4 HPV types included in the vaccine.
Data Analysis
The primary outcome of noninferiority was defined as in the
original trial: the lower bound of the multiplicity-adjusted
98.3% confidence interval for both the anti-HPV 16 and anti-
HPV 18 GMT ratios between each alternative schedule and
standard schedule was >0.50 [16]. The GMT ratios were com-
pared using a t-test. A secondary outcome of noninferiority to
non-cancer-causing HPV types 6 and 11 was also measured
using the same GMT ratio thresholds. These noninferiority
margins were based on those used in other quadrivalent
schedule, although noninferiority comparisons with the stan-
dard schedule were not performed, as a blood sample at a
similar time point was not available from the standard schedule
group. Mean age differences between girls participating in the
follow-up study—and those who did not participate (but who
were in the original trial)—were compared using ANOVA, and
ethnic and urban/rural distributions were compared using the
Cochran-Mantel-Haenszel test, adjusting for study groups. All
statistical analyses were performed using SAS software version
9.3 (SAS Institute, Cary, North Carolina). No data were
imputed; all missing data were treated as missing at random.
RESULTS
Of the 809 girls 11–13 years of age who completed the original
study per protocol, 743 were eligible for this follow-up study
(Figure 2). Due to the staggered start of the original trial, 66
girls from 2 schools vaccinated on the standard schedule were

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vaccine immune-bridging studies [8, 9]. Geometric mean anti- ineligible for the follow-up study, as the receipt of the third
body titer levels for the 4 genotypes contained in the vaccine dose of HPV vaccine was more than 32 months from the start
were also measured in samples collected at 20 months post- of the follow-up study. A total of 590 girls and their parents
dose 3 from girls vaccinated on the 0, 12, 24 month alternative provided written consent to participate in the follow-up study,

Figure 2. Trial of alternative schedules of quadrivalent human papillomavirus (HPV) vaccine in young adolescent girls, follow-up at 29–32 months,
Vietnam. *Completed all original trial study procedures and adapted from Neuzil KM, et al JAMA 2011 (see reference [16]). †Girls recruited from 2 schools
in the original trial were ineligible for the follow-up study as the receipt of the third dose of HPV vaccine was >32 months from the start of the follow-up
study.

Quadrivalent HPV Vaccine Immunogenicity • JID 2013:208 (15 October) • 1327

of which 36 withdrew after consenting; 34 of those vaccinated
on the 0, 12, 24 month schedule were lost to follow-up before
the 32-month follow-up visit; and the remaining 520 provided
a blood sample at 29–32 months post-dose 3. Samples from 2
subjects from the 0, 2, 6 month schedule were inadequate for
testing, resulting in 518 girls (ie, 64% of those who completed
the original trial) in this follow-up study (Figure 2).
The demographic information of girls participating in this
follow-up study is summarized in Table 1. The mean age and
urban/rural status of girls participating in the follow-up study
were different compared to those who did not participate, ad-
justing for vaccination schedule (both P values < .01); however,
ethnic distributions did not differ. Girls originally vaccinated
on the 0, 12, 24 month schedule were consequently older at the
32-month follow-up visit, compared to girls who received 3
doses of HPV vaccine within a 1-year schedule (0, 2, 6 months;
0, 3, 9 months; or 0, 6, 12 months).
We found the immunogenicity of quadrivalent HPV vaccine—
when delivered on any of the 3 alternative dosing schedules—was
noninferior for types 6, 11, 16, and 18 at 32 months post-dose
3, compared to girls at 29 months post-dose 3 who were vacci-
nated on the 0, 2, 6 month standard schedule (Table 2). Anti-
HPV 6, 11, 16, and 18 geometric mean titers produced were
robust even at 29 to 32 months post-dose 3 for all vaccine
administration schedules, with girls vaccinated on a 0, 12, 24
month schedule having consistently higher titers, regardless of
HPV type, than all other schedules (Figures 3 and 4). The origi-
nal trial noted that the antibody levels for all 4 HPV types prior
to the administration of dose 3 (or “pre-dose 3”) were higher
among girls vaccinated on the 0, 12, 24 month schedule in
comparison to those vaccinated on other schedules [16]. The
antibody levels 29 to 32 months post-dose 3 were similar to
those previously reported prior to the third dose (Figures 3 and
4). The interim antibody titer measure at 20 months post-dose
Table 1. Participant Demographics, Immunogenicity Follow-up Study, Vietnam
Standard schedule
At 0, 2, 6 mo
(n = 99)
Age at baseline, mean (range), y 12.0 (11.2–14.2)
Age at 29–32 mo post-dose 3, mean (range), y 15.0 (14.2–17.1)a
Ethnicity, n (%)
Muong 99 (100.0)
Kinh
Other
School location n (%)
Rural 99 (100.0)
Urban
a
For the standard schedule group, the follow-up time was 29 months post-dose 3. For the alternative schedule groups, the follow-up time was 32 months post-
dose 3.
1328 • JID 2013:208 (15 October) • LaMontagne et al
3, among girls vaccinated on the 0, 12, 24 month schedule,
showed lower titers than those measured 1 month after dose 3,
but this was still elevated from the titers measured at 32
months post-dose 3, regardless of HPV type (Figures 3 and 4).
DISCUSSION
Antibody concentrations of quadrivalent HPV vaccine among
adolescent girls produced following alternative dosing sched-
ules, including a 0, 12, 24 month vaccination schedule, were
noninferior to the concentrations generated from a standard 0,
2, 6 month vaccination schedule at 29 to 32 months post-
vaccination. These results are in contrast to the original trial
finding, in which the 0, 12, 24 month schedule was inferior to
the standard schedule for 2 of 4 genotypes at 1 month post-
dose 3 [16]. At the time, this finding was difficult to explain,
because the pre-dose 3 antibody measurements were highest
for the annual schedule. Our leading hypothesis at present
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is that the timing of the peak antibody response may differ
depending on the schedule. Thus, a 1-month post-dose 3 mea-
surement may not correlate well in assessing durability of titer
levels over time when alternative schedules are employed.
This follow-up study also showed that the genotype-specific
GMTs generated in adolescent girls in Vietnam at 29 to 32
months following the third dose were similar to those obtained
from other follow-up immunogenicity studies among adoles-
cent and young adult female populations (Table 3) [5, 8, 9, 16,
17, 20, 21, 22–24]. Table 3 summarizes the long-term immuno-
genicity studies of quadrivalent HPV vaccine in both adoles-
cent and adult female populations using the same competitive
Luminex immunoassay as our study measuring antibody levels
in milli-Merck units with standardized cutoffs. These studies il-
lustrate consistent antibody concentrations despite the differ-
ences in timing of the follow-up measurement. These studies
Alternative schedules
At 0, 3, 9 mo At 0, 6, 12 mo At 0, 12, 24 mo
(n = 135) (n = 160) (n = 124)
12.0 (11.0–13.7) 11.9 (11.0–13.6) 11.9 (11.0–13.4)
15.5 (14.5–17.2) 15.5 (14.6–17.2) 16.5 (15.6–18.0)
89 (65.9) 123 (76.9) 83 (66.9)
44 (32.6) 36 (22.5) 40 (32.3)
2 (1.5) 1 (0.6) 1 (0.8)
87 (64.4) 123 (76.9) 89 (71.8)
48 (35.6) 37 (23.1) 35 (28.2)
Table 2. Geometric Mean Antibody (GMT) Ratiosa of HPV Vaccine at 29–32 Months Post-dose 3, Alternative/Standard Schedules,
Adolescent Females, Vietnam, 2011–2012
Original Study, Intent-to-Treat Populationb
GMT ratio
1 mo. post-dose 3 all schedules (98.3% CI)
0,3,9 0,6,12
Compared to 0, 2, 6
HPV-16 0.92 (.71–1.20) 0.98 (.75–1.29)
HPV-18 0.87 (.68–1.11) 0.91 (.71–1.17)
HPV-6 1.10 (.82–1.47) 1.13 (.84–1.52)
HPV-11 0.86 (.70–1.05) 0.86 (.69–1.06)
Abbreviations: CI, confidence interval; HPV, human papillomavirus.
a
Noninferiority defined as lower-bound of the 98.3% CI for the GMT ratio is >0.50 for both HPV 16 and HPV 18, and both HPV 6 and HPV 11.
b
Adapted from Neuzil KM, et al JAMA 2011 (see reference [16]).
c
Did not meet definition of noninferiority in the original trial.
also found HPV vaccine-type antibodies depreciate over time
with plateaus observed 18–24 months post-dose 3 [8, 9, 20, 21].
Dobson et al measured adolescent antibody responses to quad-
rivalent HPV vaccine at months 18, 24, and 36 and found
similar plateaus [17, 23]. The antibody concentrations mea-
sured in our study were within similar ranges and may reflect
plateauing as well, even though the length of time between
vaccine initiation and the immunogenicity measurement
ranged between 35 and 56 months. However, the difference in
the timing of the measurements across studies must be consid-
ered when comparing results.
In a study by Block and colleagues, children 9–11 years of
age produced higher concentrations of antibodies to quadriva-
lent HPV vaccine than children 13–15 years of age; children 12
years of age fell between these 2 groups [8]. Krajden and col-
leagues have noted a similar difference between children 9–3
years of age, and individuals 15–25 years of age, even when the
younger age group was given only 2 doses of vaccine [25]. B-
cell memory and T-cell immune responses have also been dem-
onstrated to be stronger in younger adolescents [26]. We did
not find a difference in antibody responses by age in this
follow-up study, possibly because girls enrolled in the original
trial were, on average, 12 years of age at the time of the first
dose, for all 4 vaccination schedules. Girls vaccinated on the 0,
12, 24 schedule received their last dose at 14 or 15 years of age
—ages where 1-month post-dose 3 antibody concentrations
from immune-bridging studies have been demonstrated to be
lower compared to younger girls [8, 9].
To achieve maximum public health benefits, HPV vaccina-
tion programs should reach as many girls as possible before
onset of sexual activity and elicit protective immune responses
Follow-up Study Population
GMT ratio
32 mos. post-dose 3 alternative schedules/29 mos.
post-dose 3 standard schedule (98.3% CI)
0,12,24 0,3,9 0,6,12 0,12,24
Compared to 0, 2, 6
0.64 (.48–.84)c 0.90 (.68–1.20) 0.95 (.74–1.21) 1.22 (.93–1.61)
0.77 (.62–.96) 1.00 (.69–1.45) 1.02 (.74–1.40) 1.16 (.81–1.66)
0.65 (.47–.92)c 0.94 (.71–1.25) 1.04 (.82–1.33) 1.37 (1.04–1.80)
0.96 (.80–1.16) 1.04 (.79–1.38) 1.07 (.83–1.37) 1.34 (.99–1.82)
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throughout the period of sexual activity. In this regard, anti-
body concentrations measured 1 month after the third dose
among pre-sexually active adolescents aged 11–13 years may be
less clinically relevant than the long-term robustness of that re-
sponse, maintained at a level at least as high as what has been
demonstrated as efficacious in long-term follow-up studies [3,
5]. This emphasizes the importance of the finding that our 3-
dose schedule delivered annually, while inferior at 1 month,
was noninferior at >2 years after the third dose.
Our results suggest that the degradation curve of antibody
titers after vaccination with quadrivalent HPV vaccine has a
reduced slope when dosing intervals are 6 to 12 months apart,
compared to the standard schedule of 0, 2, 6 months. This may
suggest that delivering a single priming dose of HPV, followed
by a booster dose or doses, may elicit the desired antibody re-
sponse. Post hoc analysis comparing pre-dose 3 antibody
GMTs measured in our original trial with those assessed 32
months after dose 3 for the 3 alternative schedules revealed that
as the dosing schedule extended, type-specific pre-dose 3 anti-
body concentrations were either the same or higher than those
measured 32 months post-dose 3 (Figures 3 and 4). Thus, for
the 0, 3, 9 month schedule, antibody levels of HPV 6 and 18
were lower pre-dose 3 (P < .05) when compared to 32 months
post-dose 3; however, for the 0, 6, 12 month schedule, there
were no differences in the antibody concentrations for any
vaccine type between pre-dose 3 and 32 months post-dose 3
(P > .05) and for the 0, 12, 24 month schedule pre-dose 3 anti-
body concentrations were similar for HPV 6, 16, and 18
(P > .05) and higher for HPV 11 (P < .05) to those found 32
months post-dose 3. All pre-dose 3 vaccine-type antibody con-
centrations for the standard 0, 2, 6 month schedule were lower
Quadrivalent HPV Vaccine Immunogenicity • JID 2013:208 (15 October) • 1329
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Figure 3. Anti-HPV 16 and anti-HPV 18 GMT antibody response (mMU/mL) pre-dose 3, and 1 month, 20 months*, and 29–32 months post-dose 3 by
schedule†, adolescent females, Vietnam, 2007–2012. *20 month post-dose 3 measurement only assessed in Group 4 (0, 12, 24 month schedule). †All data
points restricted subjects that completed all study procedures for both the original trial and follow-up study. Abbreviations: GMT, gross mean titer; HPV,
human papillomavirus.

than those measured 29 months post-dose 3. It may be that
a longer delay for the administration of dose 2 (as long as
12 months after dose 1) allows the second dose to be the
“boosting” dose, potentially negating the need for a third dose
to perform this role. Other immunologic studies of HPV
vaccines have suggested that the mechanism of action of HPV
vaccines, due to its unique virus-like particle (VLP) structure,
and the adjuvants incorporated in them, combine to generate
an immune response that results in sufficient neutralizing
antibody and B-cell immune memory to sustain high levels of
protection [27–29].
New data from a vaccine trial suggest that efficacy against
12-month persistent HPV infection (a necessary precursor to
cervical neoplasia) can be achieved with 2 doses of bivalent
HPV vaccine, [15] with immune responses in adult women
18–25 years of age being lower than adolescents vaccinated
with the same vaccine and followed up for the same amount of
time [7, 11, 30]. Romanowski, et al found that 2 doses of biva-
lent HPV vaccine administered at 0, 6 months among adoles-
cents resulted in higher level of antibodies 24 months after the
last dose, compared to women 15–25 years of age who received
3 doses at 0, 1, and 6 months [18]. Even though these 2-dose,
long-term immunogenicity data are for bivalent HPV vaccine,
similar findings are emerging for quadrivalent HPV vaccine
(Table 3) [17, 23]. Dobson et al recently reported that adoles-
cent girls 9–13 years of age vaccinated with 2 doses of

1330 • JID 2013:208 (15 October) • LaMontagne et al

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Figure 4. Anti-HPV 6 and anti-HPV 11 GMT antibody response (mMU/mL) pre-dose 3, and 1 month, 20 months*, and 29–32 months post-dose 3 by
schedule†, adolescent females, Vietnam, 2007–2012. *20 month post-dose 3 measurement only assessed in Group 4 (0, 12, 24 month schedule). †All data
points restricted subjects that completed all study procedures for both the original trial and follow-up study. Abbreviations: GMT, gross mean titer; HPV,
human papillomavirus.

quadrivalent HPV vaccine (0, 6 months) had immune respons-
es 18, 24, and 36 months after dose 1 that were noninferior to
those measured among adult women aged 16–26 years who
were vaccinated at 0, 2, and 6 months [23].
Dosing flexibility without reduction in immunogenicity
could facilitate more feasible vaccine delivery strategies. Even
though immunogenicity does not infer efficacy, and there has
yet to be determined a correlate of protection for HPV vaccines,
[5] governments are taking action with the available evidence
base, and adjusting the recommended dosing schedule in their
national HPV vaccination programs. The provincial govern-
ment of Quebec, Canada, and the national governments of
Mexico and Colombia, have adopted a 0, 6, 60 month schedule
[31]—presupposing that if current trends in immunogenicity
hold true, the third dose may not be necessary. The provincial
government of British Columbia, Canada, started their
program with a 0, 6, 60 month schedule, and recently switched
to a 2-dose 0, 6 month schedule [32]. The Chilean govern-
ment’s national advisory committee for immunizations has rec-
ommended a 0, 12 month 2-dose schedule, based in part on the
pre-dose 3 GMT immunogenicity reported in our original trial
of alternative dosing schedules [16, 33].
Two dose schedules could be compelling for low-resource
settings, as it would reduce the financial burden of purchasing
and delivering 3 doses to adolescent girls, who may be difficult
to follow up over time [34, 35]. Costing studies have found that
the incremental financial costs of delivering HPV vaccine in
low-resource settings ranges from US$0.50 to US$3.00 per

Quadrivalent HPV Vaccine Immunogenicity • JID 2013:208 (15 October) • 1331

•1332
JID 2013:208 (15 October)

Table 3. Comparison of HPV16 and HPV18 GMT Antibody Responses, Competitive Luminex Immunoassay (cLIA), Studies of Quadrivalent HPV Vaccine, Female Adolescents and Young
Adults

Reported HPV 16 GMTs (95% CI, if known), month since first dose

Just prior
Author Reference Ages and Sex Doses Sched. to dose 3 At mo. 7 At mo. 10–13 At mo. 18 At mo. 24–25 At mo. 35–36 At mo. 41–44 At mo. 56–60 At mo. 72
Reisinger K. S., et al; [9, 22] 9–15 yo F 3 0, 2, 6 4490 1250 520.5a
Ferris D., et al
Block S. L., et al [8] 10–15 yo F 3 0, 2, 6 4697
•

Dobson S. R. M., et al [17, 23] 9–13 yo F 3 0, 2, 6 7736 (6654–8995) 1806 (1512–2156) 1726 (1506–1978) 1407 (1122–1764)
LaMontagne et al

Dobson S. R. M., et al [17, 23] 9–13 yo F 2 0, 6 7344 (6312–8544) 1579 (1322–1885) 1407 (1234–1606) 1151 (919–1441)
Neuzil K. M., et al [16] 11–13 yo F 3 0, 2, 6 668 (585–763) 5808 (4961–6799) 1072 (900–1278)
0, 3, 9 889 (791–999) 5369 (4632–6222) 966 (827–1128)
0, 6, 12 928 (756–1140) 5716 (4877–6701) 1014 (902–1140)
0, 12, 24 1572 (1366–1810) 3693 (3145–4335) 1755 (1518–2030) 1311 (1135–1514)
Villa L. L., et al [1, 3, 20] 16–23 yo F 3 0, 2, 6 3892 (3324–4558) 421 509 (436–593)b 395 (303–516)c
Wheeler C. M., et al [24] 16–23 yo F 3 0, 2, 6d 2160 407
Joura E. A., et al [5] 15–26 yo F 3 0, 2, 6 2294 460
Olsson S. E., et al [21] 16–23 yo F 3+1 0, 2, 6, 60 3870 (3157–4744) 404 (313–522)e

Reported HPV 18 GMTs (95% CI, if known), month since first dose

Just prior
Study Reference Ages/sex Doses Sched. to dose 3 At mo.7 At mo.10–13 At mo.18 At mo.24–25 At mo.35–36 At mo.41–44 At mo.56–60 At mo.72

Reisinger K. S., et al; [9, 22] 9–15 yo F 3 0, 2, 6 1071 181 71a

Ferris D., et al
Block S. L., et al [8] 10–15 yo F 3 0, 2, 6 916
Dobson S. R. M., et al [17, 23] 9–13 yo F 3 0, 2, 6 1730 (1512–1980) 238 (186–305) 264 (218–321) 237 (174–322)
Dobson S. R. M., et al [17, 23] 9–13 yo F 2 0, 6 1169 (1021–1338) 137 (107–176) 131 (108–158) 104 (76–141)
Neuzil K. M., et al [16] 11–13 yo F 3 0, 2, 6 78 (68–89) 1730 (1504–1990) 167 (133–210)
0, 3, 9 102 (88–119) 1502 (1302–1733) 170 (139–208)
0, 6, 12 137 (114–166) 1582 (1363–1835) 170 (146–197)
0, 12, 24 191 (163–224) 1336 (1192–1497) 280 (235–334) 194 (161–234)
Villa L. L., et al [1, 3, 20] 16–23 yo F 3 0, 2, 6 801 (694–925) 60 60 (49–74)b 44 (31–62)c
Wheeler C. M., et al [24] 16–23 yo F 3 0, 2, 6d 434 50
Joura E. A., et al [5] 15–26 yo F 3 0, 2, 6 462 52
Olsson S. E., et al [21] 16–23 yo F 3+1 0, 2, 6, 60 741 (577–952) 45 (32–63)e

Abbreviations: CI, confidence interval; GMT, gross mean titer; HPV, human papillomavirus.
a
Reference [22].
b
Reference [1].
c
Reference [3].
d
Placebo arm of coadministration with Hepatitis B vaccine study; reference [24].
e
Antibody response measured just prior to administration of 4th dose of HPV vaccine; reference [21].

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dose, based on annual cohorts of girls 10 years of age receiving
3 doses [36, 37]. For many governments, the administrative cost
of implementation is still too high. However, modeling studies
could estimate implementation costs of annual campaigns of
HPV vaccine for 2 doses to all girls 10 and 11 years of age (10
years of age for dose 1, and 11 years of age for dose 2), which
could inform whether this delivery strategy and schedule could
be more cost-effective than 3 doses. The financial cost may be
reduced by at least one-third, with further reduction possible
due to the need to mobilize health workers only once a year.
For countries in Latin America, which already dedicate finan-
cial and human resources to implement Vaccination of the
Americas week, [38] attaching HPV vaccine campaigns during
this annual event may provide more savings over other delivery
strategies for HPV vaccinations.
Limitations
Although we have been rigorous, we note limitations of our
study. First, not all girls who participated in the original trial
were available, or they were unable to participate in this follow-
up study; also, they were not randomly selected for participa-
tion. Those who did participate may not represent the original
trial population. In post hoc analysis, we restricted the original
trial analysis to only those girls who participated in the follow-
up study, and we found no difference in HPV 16, 18, 6, or 11
antibodies measured pre-dose 3 or 1-month post-dose 3, com-
pared to those girls who were not in the follow-up study, for all
4 vaccine-dosing schedules. Therefore, we are confident that in
terms of immune response, girls in the follow-up study are
similar to those from the original trial. Second, we did not
measure GMTs at 20 months among girls on all vaccine-dosing
schedules; therefore, the 20-month post-dose 3 measurement
provided for girls vaccinated at 0, 12, 24 months is exploratory,
and caution should be used in interpretation. Third, we did not
randomize girls to a 2-dose schedule; thus, all comparisons to
pre-dose 3 GMTs with those measured after 3 doses should be
tempered. Our post hoc analysis comparing these GMTs was
also exploratory and the variation in duration between pre-dose 3
and 32-month post-dose 3 immune measures for each of the vac-
cination schedules may make interpretation difficult. However,
the finding that pre-dose 3 GMTs were similar or higher to
GMTs at 29–32 months as dosing intervals were extended is
thought-provoking and warrants further research. Finally, an
immune correlate of protection for HPV vaccine is unknown; the
levels of HPV-type specific antibodies reported in this follow-up
study are not necessarily the same as what may be necessary to
be protected against disease endpoints. Further long-term studies
of persistent infection and cervical neoplasia should be per-
formed to understand HPV vaccine efficacy when administered
on alternative dosing schedules.
Our follow-up study of the immune response of quadrivalent
HPV vaccine administered on alternative dosing schedules has
Quadrivalent HPV Vaccine Immunogenicity
generated new evidence for dosing flexibility, suggesting that
antibody titers plateau at similar levels 29–32 months after the
third dose of vaccine, regardless of the timing of doses, and ex-
tended schedules do not produce inferior immune responses.
Our finding that antibody concentrations after 2 doses of HPV
vaccine on a 0, 12, 24 month schedule were similar to those
measured at 29 months after the third dose of a 0, 2, 6 month
schedule suggests that 2 doses of HPV vaccine delivered on an
annual 0, 12 month schedule might afford similar protection.
This hypothesis warrants exploration in a properly designed
trial. The new data generated from this study combined with
results from other follow-up studies of immunogenicity provide
an expanded understanding of immune duration that countries
can use, and have used, [31–33] when deliberating an appropri-
ate vaccination schedule for their national HPV vaccination
policy.
Downloaded from http://jid.oxfordjournals.org/ by guest on February 2, 2016
Notes
Acknowledgments. We are grateful to the girls and their families for
their participation in this study. We thank Dr Tran Thi Ai Huong, director
of Hoa Binh Provincial Medical Center, and Dr Bui Dinh Thi Dinh, former
vice director of Hoa Binh Provincial Medical Center, for their leadership
and assistance during field implementation. We acknowledge the contribu-
tions of the health staff of Hoa Binh and Kim Boi district Preventive Medi-
cine Centers, and the leaders and teachers of the 25 participating schools.
Prof Nguyen Tran Hien, director of the National Institute of Hygiene and
Epidemiology, provided leadership within the Ministry of Health, and Mr
Nguyen Hoang Anh and Ms Nguyen Thi Thu Huyen of the National Insti-
tute of Hygiene and Epidemiology were helpful in coordinating logistical
and operational support at the national level. Dr Vivien Davis Tsu gave in-
valuable comments to drafts of this article. Finally, we acknowledge the un-
fortunate death of our colleague and original coinvestigator of this study, Dr
Do Gia Canh, whose enthusiasm, tenacity, and leadership were invaluable
in the conduct of this study.
Financial support. This work was funded by a grant to PATH from the
Bill and Melinda Gates Foundation. Merck & Co. provided the immunoge-
nicity testing for no charge. Neither the funder nor Merck & Co. had a role
in the design and conduct of this study; collection, management, and inter-
pretation of the data; or preparation and approval of the article. Merck &
Co. reviewed the manuscript for proprietary information only.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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