Vaccine 40 (2022) 1198–1202
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Short communication
Binding antibody levels to vaccine (HPV6/11/16/18) and non-vaccine
(HPV31/33/45/52/58) HPV antigens up to 7 years following
immunization with either CervarixÒ or GardasilÒ vaccine
Kavita Panwar a, Anna Godi a, Clementina E. Cocuzza b, Nick Andrews c, Jo Southern d, Paul Turner e,
Elizabeth Miller d, Simon Beddows a,f,⇑
a
Virus Reference Department, UK Health Security Agency, London, UK
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
c
Statistics, Modelling and Economics Department, UK Health Security Agency, London, UK
d
Immunisation and Vaccine-Preventable Diseases Division, UK Health Security Agency, London, UK
e
Section of Paediatrics, Imperial College London, London, UK
f
Blood Safety, Hepatitis, Sexually Transmitted Infections and HIV Division, UK Health Security Agency, London, UK
b
a r t i c l e
i n f o
Article history:
Received 29 July 2021
Received in revised form 14 January 2022
Accepted 20 January 2022
Available online 1 February 2022
Keywords:
Human papillomavirus
Vaccine
Antibody
Durability
a b s t r a c t
Human Papillomavirus (HPV) bivalent (CervarixÒ) and quadrivalent (GardasilÒ) vaccines demonstrate
robust efficacy against vaccine types and cross-protection against related non-vaccine types. Here we
evaluate the breadth, magnitude and durability of the vaccine-induced antibody response against vaccine
(HPV6/11/16/18) and non-vaccine (HPV31/33/45/52/58) type antigens up to 7 years following vaccination of 12–15 year old girls in a three dose schedule and contrast these data with the levels of antibody
typically seen in natural infection. Vaccine-type antibody levels waned over the 7-year follow up period
but remained at least an order of magnitude above the typical antibody levels elicited by natural infection. Seropositivity to non-vaccine types remained high 7 years after initial vaccination, but antibody
levels approached those typically generated following natural infection. Empirical data on the breadth,
magnitude, specificity and durability of the immune response elicited by the HPV vaccines contribute
to improving the evidence base supporting this important public health intervention.
Crown Copyright Ó 2022 Published by Elsevier Ltd. All rights reserved.
1. Introduction
Bivalent (CervarixÒ) and quadrivalent (GardasilÒ) Human Papillomavirus (HPV) vaccines target prevalent oncogenic genotypes
HPV16/18, while the nonavalent vaccine (GardasilÒ9) targets additional oncogenic genotypes (HPV31/33/45/52/58) [1]. Quadrivalent
and nonavalent vaccines also target HPV6/11 which cause genital
warts. Bivalent and quadrivalent vaccines are highly efficacious
against vaccine types and induce cross-protection against related
non-vaccine types. Vaccine effectiveness studies are beginning to
confirm these observations in target populations following introduction of national immunization programmes [1,2].
We previously conducted a randomized, observer-blinded
three-dose immunogenicity trial of the bivalent and quadrivalent
vaccines in 12–15 year old girls [3]. Both vaccines induced high
⇑ Corresponding author at: UK Health Security Agency, 61 Colindale Avenue,
London NW9 5EQ, UK.
E-mail address: simon.beddows@phe.gov.uk (S. Beddows).
https://doi.org/10.1016/j.vaccine.2022.01.041
0264-410X/Crown Copyright Ó 2022 Published by Elsevier Ltd. All rights reserved.
titer neutralizing antibodies against vaccine types and lower
responses against non-vaccine types [3]. We recently conducted
a 7 year follow up study to assess the presence of neutralizing antibodies against vaccine (HPV16/18) and non-vaccine (HPV31/45)
types [4]. We now expand on these observations by presenting
data on the magnitude, breadth and durability of the binding antibody response against vaccine (HPV6/11/16/18) and non-vaccine
(HPV31/33/45/52/58) type antigens through to 7 years postvaccination and contrast these with typical natural infection antibody responses.
2. Methods
2.1. Study population and ethics
The original study protocol (ClinicalTrials.gov; NCT00956553)
and recruitment criteria have been published [3]. Briefly, 12 to
15-year-old girls were randomized to receive three doses of CervarixÒ or GardasilÒ vaccine. Serum samples were collected at
Vaccine 40 (2022) 1198–1202
K. Panwar, A. Godi, C.E. Cocuzza et al.
2.3. Statistical analysis
month (M) 0 (prior to vaccination), M2 (one month post second
dose), M7 (one month post third dose) and M12 (six months post
third dose). Participants were invited to enrol for a follow up study
(NHS Health Research Authority and the London - Hampstead
Research Ethics Committee; 16/LO/1108) [4] and following
informed consent a serum sample was collected (M84) and stored
at 80 °C. Serum samples (n = 201) were also used from a cohort
study of women (median age 33; inter-quartile range 26 – 43 years
old) following a cytological diagnosis of atypical squamous cells of
undetermined significance (ASCUS) or low-grade squamous
intraepithelial lesion (LSIL) for an estimate of natural infection
antibody levels (San Gerardo Hospital, Monza, Italy; 08/UNIMIBHPA/HPV1; No. 1191).
The sample size was limited by the response rate [4]. The proportion of seropositive samples (%; 95 %CI) and geometric mean
concentration (GMC; 95 %CI) of antibody levels were determined
for each antigen. Antibody levels below the LOD were given a censored value of half this threshold for analysis purposes. Proportions
were compared by Fisher’s exact test while comparisons of antibody levels between study arms or between vaccination and natural infection was made by the Kruskal-Wallis test. Significance was
taken at the 5% level and 95% confidence intervals used. Two-sided
significance tests were used. Stata version 15 (StataCorp, USA) was
used for statistical analyses.
3. Results
2.2. Multiplex serology
3.1. Subject characteristics
Antibody binding to non-reporter-containing L1L2 pseudovirus
antigens was evaluated on the Bio-Plex 200 platform (Bio-Plex;
Hercules, CA). Briefly, antigens representing reference sequences
for HPV6/11/16/18/31/33/45/52/58 and Bovine Papillomavirus
(BPV) [5] were coupled to spectrally-distinct microspheres and
stored as individually coupled microspheres in 0.1 M MES (2[Nmorpholino]ethanesulfonic acid), 1% bovine serum albumin, and
0.2% Proclin 300 buffer. Binding was resolved using biotinylated
goat anti-human antibody (Thermo Fisher; Rockford, IL) and
streptavidin-PE (Agilent, Santa Clara, CA).
An internal standard comprising pooled nonavalent vaccine
sera [6] was assigned arbitrary unitage (AU/mL) based upon
the magnitude of its binding against each HPV antigen and calibrated against the International Standards for HPV16 (IS16;
05/134; National Institute for Biological Standards and Control,
UK) and HPV18 (IS18; 10/140) antibodies allowing a readout
for these types in IU/mL. The internal standard was titrated
and subjected to 4PL or 5PL curve fitting (BioPlex ManagerTM)
while individual sera were titrated and dilutions with median
fluorescence intensity (MFI) signals between the lower (LLOQ)
and upper (ULOQ) limits of quantification were assigned a value
by interpolation.
The limit of detection (LOD) for each antigen was determined
using naïve [5] and pre-vaccine [3] sera (n = 146) as a source of
‘likely negative’ antibodies and three-dose vaccinee sera [3,4] as
a source of ‘likely positive’ antibodies. Receiver Operator Characteristic (ROC) analysis was performed and an interpolated 99%
specificity cut-point was applied to derive the antigen-specific
thresholds (Table 1). The ‘likely negative’ serum samples had an
apparent specificity of 99.5%. BPV was included as an irrelevant
antigen [3,5] and any sample that gave an MFI signal at the
1/100 dilution of 50% of the maximum MFI for the plate was
excluded from further analysis as a precaution. In this way, 4% of
samples in this study were excluded due to non-specific reactivity
against BPV.
Repeatability of vaccine and natural infection samples (n = 108)
resulted in a kappa statistic for the paired seropositivity data of
0.926 (95 %CI 0.901–0.952) and an r2 of 0.959 for the paired antibody levels. An internal quality control (IQC) was created by
admixing the internal standard with normal human serum (Merck;
Darmstadt, Germany). The median (inter-quartile range, IQR) antibody levels of the IQC (n = 22 runs) were as follows: HPV6 (14.5;
12.2–15.3 AU/mL); HPV11 (25.1; 20.9–27.7 AU/mL); HPV16
(45.0; 40.1–50.1 IU/mL); HPV18 (23.2; 21.2–26.3 IU/mL); HPV31
(31.2; 26.7–33.6 AU/mL); HPV33 (57.9; 48.3–62.3 AU/mL);
HPV45 (27.5; 24.0–29.3 AU/mL); HPV52 (30.5; 26.9–34.0 AU/
mL); HPV58 (50.4; 42.8–52.4 AU/mL). An HPV antibody negative
control [4] was negative in all tests.
Serum samples were collected a median 7.0 (range 6.7–7.6)
years after the first dose [4]. The median age of the vaccinees at initial study entry was 12.9 (12.0–15.9) years and 19.7 (18.2–23.6)
years old for the follow up (M84) sample. Similar numbers of CervarixÒ (n = 28) and GardasilÒ (n = 30) vaccinees enrolled in the follow up study.
3.2. Antibody binding levels
Seropositivity was 100% against vaccine-type antigens for the
bivalent (HPV16/18) and quadrivalent (HPV6/11/16/18) vaccines
from M2 to M84 (Table 1). Vaccine-type antibody levels were high
(Fig. 1) and remained at least an order of magnitude above typical
natural infection antibody levels. For example, the GMC (95 %CI) of
HPV16 antibody levels at M84 was 1,116 (827–1,505) IU/mL for
the bivalent vaccine and 210 (139–319) IU/mL for the quadrivalent
vaccine which were substantially higher (p < 0.001) than the typical levels of antibodies found in natural infection (8.7; 6.5–
11.7 IU/mL; n = 50). For HPV18, the GMC of antibody levels at
M84 was 474 (315–715) IU/mL and 88 (52–148) IU/mL for bivalent
and quadrivalent vaccines, respectively, and these were higher
(p < 0.001) than typical natural infection antibody levels (9.4;
5.9–15.2 IU/mL; n = 17). We compared bivalent and quadrivalent
vaccine HPV16/18 binding antibody levels generated in this study
with the neutralizing antibody levels (standardized to IU/mL) previously reported [4], using M12 and M84 sera (n = 112), resulting
in a clear correlation between the two assays (HPV16: Pearson’s
r = 0.863 [95 %CI 0.807–0.904] and HPV18: 0.908 [0.869–0.936]).
Non-vaccine type seropositivity rates were substantially lower
than for vaccine types. A peak (M7) seropositivity rate of 100%
was only achieved for HPV31 and HPV45 for both vaccines and
HPV58 for the bivalent vaccine and the proportion of seropositive
individuals declined over the follow up period. Non-vaccine-type
antibody levels were substantially lower than vaccine-type levels
and around those typically seen in natural infection. For example,
the GMC (95 %CI) of HPV31 antibody at M84 was 21.7 (13.8–
34.3) AU/mL for the bivalent vaccine and 10.7 (6.9–16.6) AU/mL
for the quadrivalent vaccine and these were slightly above
(p = 0.018 for bivalent) or similar to (p = 0.398 for quadrivalent)
the typical levels of natural infection antibodies (9.0; 6.4–12.8
AU/mL; n = 44). For HPV45, the antibody levels at M84 were 11.5
(6.9–19.0) AU/mL and 4.3 (3.0–6.0) AU/mL for bivalent and quadrivalent vaccines, respectively, and these were similar to (p = 0.915
for bivalent) or below (p = 0.012 for quadrivalent) the typical levels
of natural infection antibodies (10.9; 6.0–19.8 AU/mL; n = 9). There
are no International Standards for types other than HPV16 and
1199
K. Panwar, A. Godi, C.E. Cocuzza et al.
Vaccine 40 (2022) 1198–1202
Table 1
Seropositivity and geometric mean concentration (GMC; 95 %CI) of antibody levels against vaccine and non-vaccine type HPV antigens.
Seropositivity n/N (%; 95 %CI)
GMC (95 %CI)
à
HPV
Month
Cervarix
Gardasil
p value
Cervarix
Gardasil
p valueà
6
M0
M2
M7
M12
M84
0/26
0/26
2/27
2/27
3/28
(0; 0–13%)
(0; 0–13%)
(7; 1–24%)
(7; 1–24%)
(11; 2–28%)
0/26 (0; 0–13%)
28/28 (100; 88–100%)
28/28 (100; 88–100%)
29/29 (100; 88–100%)
29/29 (100; 88–100%)
1.000
<0.001
<0.001
<0.001
<0.001
2.2
2.2
3.4
2.5
2.9
(2.2–2.2)
(2.2–2.2)
(1.8–6.3)
(2.1–3.0)
(2.0–4.1)
2.2 (2.2–2.2)
143 (89.4–228)
1,048 (729–1,505)
311 (213–453)
81.2 (55.8–118)
1.000
<0.001
<0.001
<0.001
<0.001
11
M0
M2
M7
M12
M84
0/26
0/26
3/27
5/27
2/28
(0; 0–13%)
(0; 0–13%)
(11; 2–29%)
(19; 6–38%)
(7; 1–24%)
0/26 (0; 0–13%)
28/28 (100; 88–100%)
28/28 (100; 88–100%)
29/29 (100; 88–100%)
29/29 (100; 88–100%)
1.000
<0.001
<0.001
<0.001
<0.001
2.9
2.9
4.9
4.8
3.6
(2.9–2.9)
(2.9–2.9)
(2.6–9.3)
(2.9–7.7)
(2.7–4.8)
2.9 (2.9–2.9)
224 (134–375)
1,622 (1,146–2,295)
753 (508–1,117)
133 (89.3–198)
1.000
<0.001
<0.001
<0.001
<0.001
16
M0
M2
M7
M12
M84
0/26 (0; 0–13%)
26/26 (100; 87–100%)
27/27 (100; 87–100%)
27/27 (100; 87–100%)
28/28 (100; 88–100%)
0/26 (0; 0–13%)
28/28 (100; 88–100%)
28/28 (100; 88–100%)
29/29 (100; 88–100%)
29/29 (100; 88–100%)
1.000
1.000
1.000
1.000
1.000
0.9 (0.9–0.9)
457 (252–829)
4,844 (3,187–7,362)
4,054 (2,740–5,999)
1,116 (827–1,505)
0.9 (0.9–0.9)
370 (230–595)
1,901 (1,331–2,714)
1,270 (833–1,937)
210 (139–319)
1.000
0.275
0.002
<0.001
<0.001
18
M0
M2
M7
M12
M84
0/26 (0; 0–13%)
26/26 (100; 87–100%)
27/27 (100; 87–100%)
27/27 (100; 87–100%)
28/28 (100; 88–100%)
0/26 (0; 0–13%)
28/28 (100; 88–100%)
28/28 (100; 88–100%)
29/29 (100; 88–100%)
29/29 (100; 88–100%)
1.000
1.000
1.000
1.000
1.000
1.6 (1.6–1.6)
514 (318–830)
4,823 (3,302–7,046)
1,804 (1,067–3,050)
474 (315–715)
1.6 (1.6–1.6)
192 (122–300)
1,366 (927–2,013)
550 (343–881)
88.0 (52.3–148)
1.000
0.003
<0.001
0.003
<0.001
31
M0
M2
M7
M12
M84
0/26 (0; 0–13%)
13/26 (50; 30–70%)
27/27 (100; 87–100%)
27/27 (100; 87–100%)
27/28 (96; 82–100%)
0/26 (0; 0–13%)
18/28 (64; 44–81%)
28/28 (100; 88–100%)
29/29 (100; 88–100%)
27/29 (93; 77–99%)
1.000
0.409
1.000
1.000
1.000
0.9 (0.9–0.9)
2.6 (1.6–4.2)
194 (123–305)
57.6 (35.6–93.1)
21.7 (13.8–34.3)
0.9 (0.9–0.9)
3.2 (2.0–5.1)
70.7 (49.5–101.1)
32.1 (20.9–49.2)
10.7 (6.9–16.6)
1.000
0.478
0.002
0.065
0.023
33
M0
M2
M7
M12
M84
0/26 (0; 0–13%)
0/26 (0; 0–13%)
22/27 (81; 62–94%)
16/27 (59; 39–78%)
14/28 (50; 31–69%)
0/26 (0; 0–13%)
1/28 (4; 0–18%)
21/28 (75; 55–89%)
13/29 (45; 26–64%)
10/29 (34; 18–54%)
1.000
1.000
0.746
0.300
0.289
2.6 (2.6–2.6)
2.6 (2.6–2.6)
15.0 (9.4–24.0)
6.9 (4.7–10.2)
6.8 (4.3–10.5)
2.6
2.6
9.5
4.7
3.9
(2.6–2.6)
(2.5–2.8)
(6.6–13.8)
(3.5–6.3)
(3.1–5.0)
1.000
0.822
0.186
0.142
0.104
45
M0
M2
M7
M12
M84
0/26 (0; 0–13%)
16/26 (62; 41–80%)
27/27 (100; 87–100%)
25/27 (93; 76–99%)
24/28 (86; 67–96%)
0/26 (0; 0–13%)
10/28 (36; 19–56%)
28/28 (100; 88–100%)
26/29 (90; 73–98%)
16/29 (55; 36–74%)
1.000
0.101
1.000
1.000
0.020
1.8 (1.8–1.8)
4.7 (3.1–7.1)
97.0 (60.6–155.4)
28.1 (16.7–47.4)
11.5 (6.9–19.0)
1.8 (1.8–1.8)
2.9 (2.2–3.8)
29.2 (21.0–40.4)
9.4 (6.7–13.1)
4.3 (3.0–6.0)
1.000
0.083
<0.001
<0.001
0.003
52
M0
M2
M7
M12
M84
0/26 (0; 0–13%)
4/26 (15; 4–35%)
26/27 (96; 81–100%)
22/27 (81; 62–94%)
23/28 (82; 63–94%)
0/26 (0; 0–13%)
3/28 (11; 2–28%)
23/28 (82; 63–94%)
13/29 (45; 26–64%)
13/29 (45; 26–64%)
1.000
0.699
0.193
0.006
0.006
0.7 (0.7–0.7)
0.8 (0.7–1.0)
17.1 (10.5–28.0)
3.8 (2.3–6.2)
4.1 (2.5–6.9)
0.7
0.8
4.4
1.5
1.8
(0.7–0.7)
(0.7–1.0)
(2.8–6.9)
(1.0–2.4)
(1.1–3.0)
1.000
0.795
<0.001
0.003
0.013
58
M0
M2
M7
M12
M84
0/26 (0; 0–13%)
2/26 (8; 1–25%)
27/27 (100; 87–100%)
24/27 (89; 71–98%)
24/28 (86; 67–96%)
0/26 (0; 0–13%)
14/28 (50; 31–69%)
27/28 (96; 82–100%)
26/29 (90; 73–98%)
19/29 (66; 46–82%)
1.000
0.001
1.000
1.000
0.123
0.7 (0.7–0.7)
0.8 (0.7–0.9)
19.9 (13.4–29.6)
5.6 (3.6–8.8)
6.9 (3.8–12.6)
0.7 (0.7–0.7)
1.4 (1.0–1.8)
11.1 (7.2–17.1)
4.2 (2.9–6.1)
2.8 (1.8–4.5)
1.000
0.007
0.047
0.231
0.035
à p values < 0.05 highlighted in bold type. Antibody levels less than the Limit of Detection (LOD) for each antigen (HPV6 4.4 AU/mL; HPV11 5.9 AU/mL; HPV16 1.7 IU/mL;
HPV18 3.3 IU/mL; HPV31 1.9 AU/mL; HPV33 5.1 AU/mL; HPV45 3.7 AU/mL; HPV52 1.4 AU/mL; HPV58 1.5 AU/mL) were censored and assigned a value of half the LOD for
calculation purposes.
Vaccine-type antibody levels remained an order of magnitude
above the typical levels of antibody elicited by natural infection.
Bivalent HPV16/18 antibodies are maintained at higher levels compared to the quadrivalent vaccine within the context of head to
head studies [3,4,7] and cohort studies [10,11]. We report here
HPV16/18 antibody levels in international units and demonstrate
a good correlation between binding (this study) and neutralizing
[4] antibody levels, as others have done recently [12], allowing
comparisons of antibody levels between studies that also report
in standardised unitage.
Non-vaccine type seropositivity rates were substantially lower
than for vaccine types but nevertheless a significant proportion
of vaccinees had detectable antibody against non-vaccine type
antigens up to 7 years following vaccination. Few studies have
compared antibody responses against non-vaccine types for both
vaccines after long term follow up and even fewer in a head-to-
HPV18 so non-vaccine-type antibody levels could not be formally
benchmarked.
4. Discussion
All participants remained seropositive to vaccine-incorporated
types for the bivalent and quadrivalent vaccine throughout 7 years
of follow up. There have been few long-term follow up studies that
have compared vaccine immune responses directly in the context
of a randomized, head-to-head trial in the target age group for vaccination. A lower HPV18 seropositivity rate for the quadrivalent
vaccine has been reported in a 5 year study of both vaccines in
18 to 26-year-old women [7]. Lower HPV18 seropositivity rates
have also been reported in individual studies of adolescents [8]
or 16 to 23-year-old women [9] after 8–9 years following receipt
of three doses of quadrivalent vaccine.
1200
Vaccine 40 (2022) 1198–1202
K. Panwar, A. Godi, C.E. Cocuzza et al.
HPV11
1000
1000
1000
100
10
GMC (IU/mL)
10000
100
10
1
1
0
12
24
36
48
60
72
84
12
10
24
36
48
60
72
84
96
0
1000
1000
1
GMC (AU/mL)
1000
GMC (AU/mL)
10000
10
100
10
24
36
48
60
72
84
96
0
12
Months post-1st dose
HPV45
24
36
48
60
72
84
0
96
GMC (AU/mL)
1000
GMC (AU/mL)
1000
100
10
1
24
36
48
60
72
Months post-1st dose
84
96
96
24
36
48
60
72
84
96
84
96
HPV58
1000
12
12
HPV52
10000
0
84
Months post-1st dose
10000
1
72
10
10000
10
60
100
Months post-1st dose
100
48
1
1
12
36
HPV33
HPV31
10000
100
24
Months post-1st dose
10000
0
12
Months post-1st dose
HPV18
GMC (IU/mL)
100
1
0
96
Months post-1st dose
GMC (AU/mL)
HPV16
10000
GMC (AU/mL)
GMC (AU/mL)
HPV6
10000
100
10
1
0
12
24
36
48
60
72
Months post-1st dose
84
96
0
12
24
36
48
60
72
Months post-1st dose
Fig. 1. Binding antibody levels over time. GMC (95 %CI) of bivalent (Blue) and quadrivalent (Red) vaccine antibody levels from M7, M12 and M84 following initial vaccine
dose. Dotted line represents the LOD for each antigen: HPV6 4.4 AU/mL; HPV11 5.9 AU/mL; HPV16 1.7 IU/mL; HPV18 3.3 IU/mL; HPV31 1.9 AU/mL; HPV33 5.1 AU/mL; HPV45
3.7 AU/mL; HPV52 1.4 AU/mL; HPV58 1.5 AU/mL. Bold dashed line represents the GMC of antibody levels found in a cohort of naturally infected adult women: HPV6 17.1 AU/
mL; HPV11 10.4 AU/mL; HPV16 8.7 IU/mL; HPV18 9.4 IU/mL; HPV31 9.0 AU/mL; HPV33 10.2 AU/mL; HPV45 10.9 AU/mL; HPV52 5.0 AU/mL; HPV58 7.2 AU/mL.
rated genotypes and the long-term effectiveness is uncertain [19].
There are no defined correlates of protection for HPV vaccination,
although natural infection antibody levels have often been used
as a benchmark for gauging vaccine immunity. Antibody responses
elicited during natural infection appear to be quantitatively and
qualitatively different from that of vaccinees, although there are
suggestions that they can be modestly protective [20].
The nonavalent GardasilÒ9 vaccine has demonstrated broad
efficacy and will likely be adopted by national immunization programmes in time [1]. It is unlikely that the limited degree of crossprotection afforded by the bivalent and quadrivalent vaccines will
be a match for the broad coverage of the high valency nonavalent
vaccine [18,19]. However, tens of millions of adolescent girls have
already been vaccinated with the bivalent or quadrivalent vaccine,
and a better understanding of vaccine immunity, particularly the
breadth, magnitude and durability of the antibody responses, is
warranted.
This study has several strengths including the durability of the
immune response to both vaccines in participants at the target age
for vaccination in national immunization programmes; evaluation
in the context of a randomized, head-to-head trial; the reporting of
vaccine and non-vaccine-type antibody levels 7 years following
initial vaccination, the comparison with natural infection antibody
head study format. Seropositivity rates against HPV31/45 reported
here were higher than the rates seen in a head-to-head study of 18
to 26 year-old-women 2 years after initial vaccination [13]. Serum
collected within the Finnish Maternity Cohort demonstrate that a
substantial proportion of individuals were seropositive for nonvaccine type antibodies up to 12 years following three-dose vaccination [10,11].
Non-vaccine-type antibody levels were substantially lower than
those generated against vaccine types and in most cases were
indistinguishable from the typical levels of antibody elicited following natural infection. Low level antibody responses against
HPV31/45 have been reported for 2 years following vaccination
of 18 to 26 year-old-women with bivalent or quadrivalent vaccine
[13] and up to 10 years following vaccination of adolescent girls
with bivalent vaccine [14]. Cohort studies support a durable but
low level antibody response against non-vaccine types in adolescent girls following three doses of bivalent or quadrivalent vaccine
[10,11,15].
Vaccine-type antibody levels in a two-dose schedule are noninferior to those of a three-dose schedule but this may not be the
case for non-vaccine-type antibody [14,16–18]. Vaccine-induced
cross-protection appears to be limited to a few genotypes
(HPV31, HPV33 and HPV45) closely related to the vaccine incorpo1201
K. Panwar, A. Godi, C.E. Cocuzza et al.
Vaccine 40 (2022) 1198–1202
levels and the reporting of vaccine type (HPV16 and HPV18) antibody levels in International Units. Shortcomings in this study
include the relatively low number of responders to the follow up
study which inevitably impacts on the precision of some of the
estimates. In addition, natural infection sera were derived from a
single cohort which may not be representative of all HPV natural
infection immune responses and likely include incident, persistent
and cleared infections which may differ quantitatively in their
antibody response. Nevertheless, these data provide additional
empirical support for the observed effectiveness of the HPV vaccines, particularly against non-vaccine types.
[3] Draper E, Bissett SL, Howell-Jones R, Waight P, Soldan K, Jit M, et al. A
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Gardasil((R)) Human Papillomavirus vaccines in 12–15 year old girls. PLoS
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(R) vaccine. Vaccine. 2019;37:2455–62.
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et al. Comparison of long-term immunogenicity and safety of human
papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18
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neutralising antibodies induced by bivalent or quadrivalent HPV vaccines and
correlation with efficacy: a combined follow-up analysis of data from two
randomised, double-blind, multicentre, phase 3 trials. Lancet Infect Dis
2021;21(10):1458–68.
[11] Kann H, Lehtinen M, Eriksson T, Surcel H-M, Dillner J, Faust H. Sustained crossreactive antibody responses after human papillomavirus vaccinations: up to
12 years follow-up in the finnish maternity cohort. J Infect Dis 2021;223
(11):1992–2000.
[12] Tsang SH, Basu P, Bender N, Herrero R, Kemp TJ, Kreimer AR, et al. Evaluation of
serological assays to monitor antibody responses to single-dose HPV vaccines.
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[13] Einstein MH, Baron M, Levin MJ, Chatterjee A, Fox B, Scholar S, et al.
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[15] Hoes J, Pasmans H, Knol MJ, Donken R, van Marm-Wattimena N, Schepp RM,
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[16] Safaeian M, Porras C, Pan Y, Kreimer A, Schiller JT, Gonzalez P, et al. Durable
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[18] Stanley M, Joura E, Yen GP, Kothari S, Luxembourg A, Saah A, et al. Systematic
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Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
Special thanks to the study participants without whom this study
would not have been possible and we are grateful to the NVEC vaccine research nurses and other staff for the execution of this study.
We thank Busayo Elegunde, Ayesha Febis and Farida Abdulkadir for
their excellent technical assistance with the execution of this
study.
We are indebted to Prof. John T. Schiller and Dr. Chris Buck
(National Cancer Institute, Bethesda, MD., U.S.A.) for the psheLL
L1L2 clones used to make the pseudoviruses in this study.
We thank Drs Ligia Pinto and Troy Kemp of Frederick National
Laboratory for Cancer Research, Leidos Biomedical Research, Inc.
MD., U.S.A. as the source of nonavalent vaccine serum used to
make the standards and IQC.
Author contributions
Original study design: KP AG NA JS PT EM SB. Data generation:
KP AG. Data analysis: KP NA SB. Material contribution: CEC EM.
Manuscript preparation and approval: All authors.
Funding
This work was supported by the UK Health Security Agency.
This publication is independent research part funded by the
National Institute for Health Research Policy Research Programme
(‘‘Vaccine Evaluation Consortium Phase II”, 039/0031). The views
expressed in this publication are those of the author(s) and not
necessarily those of the NHS, the National Institute for Health
Research or the Department of Health and Social Care.
References
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vaccine development and implementation. Lancet Oncol 2015;16(5):e206–16.
[2] Drolet M, Bénard É, Pérez N, Brisson M, Ali H, Boily M-C, et al. Population-level
impact and herd effects following the introduction of human papillomavirus
vaccination programmes: updated systematic review and meta-analysis.
Lancet 2019;394(10197):497–509.
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