Vaccine xxx (xxxx) xxx

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Antibody responses to prophylactic quadrivalent human papillomavirus

vaccine at 48 months among HIV-infected girls and boys ages 9–14 in
Kenya, Africa
Nelly Mugo a,b,c,⇑, Linda O. Eckert b,d, Lydia Odero c, Stephen Gakuo c, Kenneth Ngure b,e,
Connie Celum b,f,g, Jared M. Baeten b,f,g, Ruanne V. Barnabas b,f,g, Anna Wald f,g,h,i
a
Kenya Medical Research Institute, Center for Clinical Research, Kenya
b
Department of Global Health, University of Washington, Seattle, WA, USA
c
Partners in Health Research and Development, Kenya
d
Department of Obstetrics and Gynaecology, University of Washington, WA, USA
e
Department of Community Health, Jomo Kenyatta University of Agriculture and Technology, Kenya
f
Departments of Medicine, University of Washington, Seattle, WA, USA
g
Department of Epidemiology, University of Washington, Seattle, WA, USA
h
Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
i
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: HIV infected children remain at increased risk of HPV associated malignancies as they initiate
Received 9 June 2020 sexual activity. Though they mount a vigorous immune response to the quadrivalent human papillo-
Received in revised form 5 November 2020 mavirus (QHPV-6, -11,-16, and -18; GardasilÒ) vaccine, durability of the immune response is uncertain.
Accepted 7 December 2020
We assessed antibody responses to HPV 6, -11, -16 and -18 for up to 48 months following administration
Available online xxxx
of quadrivalent human papillomavirus vaccine in HIV-infected girls and boys ages 9–14 years in Kenya.
Design: Of 178 girls and boys who had previously received three doses of the quadrivalent HPV vaccine,
Keywords:
176 enrolled into extended follow up for 4 years. HPV antibodies to -6, -11, -16 and -18 were measured at
HIV infected
Adolescents
24, 36 and 48 months after the first vaccine dose using the total immunoglobulin G immunoassay (IgG
HPV vaccine LIA). We evaluated the magnitude and trend in HPV vaccine response and the effect of plasma HIV-1
Africa RNA on HPV vaccine response from month 24 to month 48 of follow up.
Results: At re-enrollment, 24 months after initial vaccination, median age of participants was 14 years
(range 11–17); 167 (95%) were receiving antiretroviral therapy and 110 (66%) had plasma HIV
RNA < 40 copies/mL. The rate of HPV seropositivity at 48 months was 83% for HPV-6; 80% for HPV-11;
90% for HPV-16; and 77% for HPV-18. There was a plateau in mean log10 HPV-specific antibody titer
between month 24 and 48. The mean log10 HPV-type specific antibody titer for children with unde-
tectable HIV viral load (<40) at the time of vaccination consistently remained higher for the 48 months
of follow up compared to children with detectable viral load.
Conclusion: Children with HIV infection may retain long term antibody response following HPV immu-
nization. Further work to define whether HIV-infected children are protected from HPV acquisition with
low levels of HPV antibodies is needed.
Ó 2020 Published by Elsevier Ltd.

1. Introduction human papillomavirus (HPV) serotypes [1–3]. Since vaccine licen-

There is indisputable evidence of the efficacy of the bivalent,
quadrivalent and nonavalent HPV vaccines against vaccine specific
⇑ Corresponding author at: Center for Clinical Research (CCR), Kenya Medical
Research Institute (KEMRI), International Clinical Research Center, Department of
Global Health, University of Washington, Box 359927, 325 Ninth Avenue, Seattle,
WA 98104, USA.
E-mail address: rwamba@uw.edu (N. Mugo).
sure in 2006, an extensive body of literature has documented up to
10 years of sustained immunogenicity [4], with effective preven-
tion of HPV infection and squamous intra-epithelial lesions [5,6].
Further, HPV immunization has demonstrated population level
vaccine impact [7,8]. For example, a recent metaanalysis of HPV
vaccine programs among girls ages 13–18 years reported 83%
reduction in HPV-16 and -18, 5 years post initiation of the program
[9]. HPV vaccine coverage has continued to rise with an estimate of

https://doi.org/10.1016/j.vaccine.2020.12.020
0264-410X/Ó 2020 Published by Elsevier Ltd.

Please cite this article as: N. Mugo, L.O. Eckert, L. Odero et al., Antibody responses to prophylactic quadrivalent human papillomavirus vaccine at 48 months
among HIV-infected girls and boys ages 9–14 in Kenya, Africa, Vaccine, https://doi.org/10.1016/j.vaccine.2020.12.020
N. Mugo, L.O. Eckert, L. Odero et al.
at least 85 countries that have implemented HPV vaccine programs
and over 260 million doses distributed as of 2016 [10].
HIV-1 infection is associated with increased risk for HPV-
associated cancers [11–13], which may be due to increased persis-
tence [14] and replication of HPV [15,16]. Invasive cervical cancer
and anal cancer rates remain high in the era of antiretroviral ther-
apy (ART) among people living with HIV compared to general pop-
ulations [17], although regular screening and treatment for high
grade intraepithelial lesions partly mitigates risk of cervical cancer
[18]. A recent systemic review found evidence for reduced preva-
lence of high risk (HR)-HPV and cervical intraepithelial lesions
(CIN2+) with early initiation and adherence to ART compared to
ART naïve women [19].
Since the risk of HPV exposure persists throughout a person’s
sexual life, the duration of protection, especially when the vaccine
is given in the pre-adolescent period, is critical to vaccine effective-
ness. Among women aged 18–26 years in extended follow-up fol-
lowing enrollment in bivalent [20], quadrivalent [21,4,22] and the
nanovalent [23] HPV vaccine trials, effective protection from high
grade cervical intraepithelial lesions has been demonstrated for
up to 10 years, especially among women naïve to the vaccine
HPV type at vaccination. Prior reports on the immunogenicity of
the HPV vaccine among children with HIV was mostly limited to
7 months post initial vaccine dose [24–28]. These studies demon-
strated safety and seroconversion rates above 90%, albeit the anti-
HPV serotype specific antibody geometric mean were lower than
those documented among age cohort HIV-negative individuals.
To provide longer-term immunogenicity data, we evaluated per-
sistence of HPV antibody response among a cohort of boys and girls
living with HIV ages 9–14 years up to 48 months after a three-dose
vaccine schedule of the quadrivalent HPV (QHPV) vaccine.
2. Methods
2.1. Study population
The original study of the QHPV vaccine enrolled and followed
100 HIV-1 infected girls and 80 boys ages 9–14 years for 12 months,
in Thika, Kenya [28]. Exclusion criteria for the original protocol
included undisclosed HIV status by parent to child, and presence
of medical conditions that precluded vaccination. The study began
enrollment in May 2013; in September 2015, 178 participants
were approached for re-enrollment and extended follow-up
through 48 months, and 176 girls and boys provided assent with
parental consent for study participation. Eligibility required receipt
of three doses of QHPV vaccine as part of prior participation in the
parent trial [28], parental/guardian consent and participant assent,
and willingness to continue extended follow-up. The Kenyatta
National Hospital Ethics Review Committee and the University of
Washington Ethics Review Committees approved the study.
2.2. Procedures
At enrollment for extended follow up and during bi-annual
clinic visits, medical evaluation through history and physical
examination were done, with clinical assessment for HIV disease
stage using WHO criteria. HIV RNA was quantified annually and
at study exit visit (month 48) using the M2000SP Abbott real-
time HIV assay at the KEMRI HIV Research Laboratory, Kisumu
and CD4 cell count was performed at the Clinical Trial Research
Laboratory (CTRL), Department of Obstetrics and Gynaecology,
University of Nairobi.
Serum samples were collected at enrollment in the extended
follow up phase, which was approximately 24 month after the ini-
tial vaccine dose, and at months 36 and 48 for serologic testing of
2
Vaccine xxx (xxxx) xxx
antibodies against HPV L1 capsid protein using IgG Luminex-
Immunoassay (IgG-LIA) at the Merck laboratories [29]. Serological
measurements of type-specific HPV immune response were calcu-
lated from measurements of titers to provide geometric mean
titers (GMT).
2.3. Statistical analysis
We assessed baseline socio-demographic characteristics and
HIV-1 disease status at the enrollment, month 36 and 48 visit for
all study participants. Our outcomes of interest included the magni-
tude and duration of HPV type specific immune response and the
corresponding HPV-type specific seropositivity at month 24, 36,
48 post first vaccine dose. We also assessed the effect of plasma
HIV-1 RNA at the time of vaccination on HPV vaccine response over
time. A participant was defined as HPV seropositive if their anti-HPV
serum IgG LIA level in milli-Merck Units/ml (mMu/mL) was equal to
or greater than predetermined seropositivity according to different
serum cut-off points (SSCO) [30]: 9 for HPV-6, 6 for HPV-11, 5 for
HPV-16 and 5 for HPV-18 [29]. The magnitude and duration of anti-
body response was measured with HPV IgG type-specific antibody
expressed as milli-Merck per milliliter (mMU/ml) and the corre-
sponding seropositivity rates for HPV-6, -11, -16 and -18 at month
24, 36 and 48 after initial HPV vaccine dose. We used GMT to quan-
tify the magnitude of the average HPV-type specific antibody
response per each time point of measurement. We computed the
seroconversion rates for each type of HPV as a proportion of the
raw numbers of persons with HPV antibody response  SSCO for
HPV-type specific from total number of persons who had their sam-
ple taken and tested for that specific HPV antibody response. Sero-
logical testing of antibodies against HPV for samples collected at
month 7 & 12 was done using Competitive Luminex-
Immunoassay (cLIA) [28] and therefore could not be combined with
data from month 24 to 48. This analysis was limited to data obtained
during the month 24 visit post vaccination and measures obtained
during the extended follow up. To evaluate whether HIV-1 disease
severity influenced vaccine immunogenicity over time, we used lin-
ear mixed-effects models to assess for potential association
between log10 HPV antibody titers for each type (6, 11, 16 and 18)
and HIV-1 viral load status at the time of vaccination. HIV viral load
status was defined as undetectable if the HIV viral load was < 40
copies/ml and detectable if the viral load was  40 copies/ml.
We randomly selected 50 children using simple random sam-
pling method to illustrate their individual HPV-type specific anti-
body response profiles by their HIV-viral load status over the
follow-up period between month 24 and 48. Each child had equal
selection probability.
3. Results
Among 180 girls and boys enrolled in the initial protocol, 178
children completed initial 12 month of study follow-up and 176
participants (98 girls and 78 boys) consented to extended study
follow up (Fig. 1). The median time between the first dose of vac-
cine and enrollment for extended follow up was 25 months (range
23–29). The median age at re-enrollment was 14 years (range 11–
17 years) (Tables 1a and 1b). One hundred sixty-seven (94.9%) par-
ticipants were receiving ART and 66 (37.5%) had a plasma HIV
RNA > 40 copies/mL. The median CD4 cell count was 701 (IQR
520–943) with 6 (3.5%) children who had CD4 cell count < 200
cell/mm3 (see Tables 1a).
The rate of seropositivity at month 48 of follow up was 83% for
HPV-6; 80% for HPV-11; 90% for HPV-16 and 77% for HPV-18;
(Table 2). The percentage decline in HPV-serotype specific anti-
body immune response between month 24 and 48 was 7%, 5%,
N. Mugo, L.O. Eckert, L. Odero et al. Vaccine xxx (xxxx) xxx

Fig 1. Schematic representation of the study.

Table 1a
Demographic characteristics at re-enrollment (Month 24).

Girls (N = 98) Boys (N = 78) Total (N = 176)

Age, years, median (range) 14 (11–17) 14 (11–17) 14 (11–17)
WHO clinical disease stage
Stage 1 18 (18%) 12 (15%) 30 (17%)
Stage 2 37 (38%) 30 (38%) 67 (38%)
Stage 3 40 (41%) 34 (44%) 74 (42%)
Stage 4 3 (3%) 1 (1%) 4 (2%)
Currently on ART 90 (91.8%) 77 (98.7%) 167 (94.9%)
On ART: HIV RNA copies/mL
<40 58 (64%) 52 (68%) 110 (66%)
40–400 6 (7%) 5 (6%) 11 (7%)
>400–10,000 15 (17%) 12 (16%) 27 (16%)
>10,000 11 (12%) 8 (10%) 19 (11%)
Not on ART 8 (8.2%) 1 (1.3%) 9 (5.1%)
VL, median (range) 11,369 (900–44,214) 148,290 (148,290–148,290) 17,094 (900, 148,290)
CD4 count cells/mm3
CD4 count, median (IQR) 702 (499–925) 699 (538–946) 701 (520–943)
CD4 count < 200 3 (3.2%) 3 (3.9%) 6 (3.5%)
CD4 count: 200–500 21 (22.3%) 11 (14.3%) 32 (18.7%)
CD4 count: >500 70 (74.5%) 63 (81.8%) 133 (77.8%)
BMI < 5th percentile 2 (2.0%) 6 (7.7%) 8 (4.6%)

Table 1b
HIV Status at different time points.

HIV Status Initial enrolment (N = 180) 24 months (N = 176) 36 months (N = 174) 48 months (N = 164)
Viral load copies/mL
<40 92 (51%) 110 (63%) 103 (60%) 101 (62%)
40 87 (49%) 66 (37%) 68 (40%) 61 (38%)
CD4 Count cells/mm3
<500 48 (27%) 38 (22%) 38 (23%) 54 (35%)
500 131 (73%) 133 (78%) 127 (77%) 102 (65%)
WHO Staging
Stage 1 37 (20%) 30 (17%) 29 (17%) 39 (24%)
Stage 2 64 (36%) 67 (38%) 66 (38%) 59 (37%)
Stage 3 74 (41%) 74 (42%) 71 (41%) 56 (35%)
Stage 4 5 (3%) 4 (2%) 6 (3%) 6 (8%)

3
N. Mugo, L.O. Eckert, L. Odero et al. Vaccine xxx (xxxx) xxx

Table 2
Geometric mean titers of HPV antibodies and rates of seropositivity for IgG.

24 months 36 months 48 months % difference

(N = 176) (N = 174) (N = 164) (M-24 & M-48)
HPV 6 GMT 61 48 38
(95% CI) (49, 76) (38, 60) (30, 48)
Proportion Positive 90% 86% 83% 7%
(155/172) (140/162) (132/159)
1
Gardasil package Insert GMT 156 129
(95% CI) (136–180) (116–145)
HPV 11 GMT 42 30 24
(95% CI) (33, 53) (23, 38) (18, 31)
Proportion Positive 85% 83% 80% 5%
(147/172) (135/162) (127/159)
1
Gardasil package Insert GMT 218 148
(95% CI) (188–252) (131–167)
HPV 16 GMT 243 170 137
(95% CI) (183, 322) (126, 230) (100, 187)
Proportion Positive 96% 93% 90% 6%
(165/172) (151/162) (143/159)
1
Gardasil package Insert GMT 944 642
(95% CI) (804–1108) (562–733)
HPV 18 GMT 39 29 23
(95% CI) (29, 52) (21, 39) (17, 31)
Proportion Positive 82% 78% 77% 5%
(141/172) (126/162) (122/159)
1
Gardasil package Insert GMT 138 87
(95% CI) (115–165) (75–101)
1
Girls age group 9–15 years HIV-uninfected Cohort; GMT for 9–15 year old girls ended prior to month 48.

Fig 2a. Log10 HPV Antibody Titers (anti HPV-6 and HPV-11) over 48 months post vaccination.

4
N. Mugo, L.O. Eckert, L. Odero et al. Vaccine xxx (xxxx) xxx

6% and 5% for HPV 6, -11, -16 and -18, respectively. At month 48,
HPV antibody titer levels were below standard cut-off levels for
seropositivity for all 4 HPV types for 7 unique children, for HPV-
16 and 18 for 14 children and for any HPV type for 49 children.
The majority of the HIV-infected children retained antibody
response to one or more of the four HPV types. Of the 7 non-
responders to all 4 QHPV types, only one had undetectable HIV
viral load and of the 49 non-responders to any of the four HPV
types, 7 had undetectable viral load.
HPV antibody response and HIV viral load were measured at
month 24, 36 and 48 after dose one of vaccination. The proportion
of children with plasma HIV RNA < 40 copies/mL ranged between
51 and 64% over the 24–48 months of follow-up (Table 1b). The
change in HPV titers from month 24 to month 48 was not statisti-
cally significant for any of the 4 QHPV serotypes, with little decline
in log10 HPV-type specific antibody titers (Figs. 2a and 2b). Chil-
dren with undetectable HIV viral load at the time of the initial vac-
cination consistently retained higher log10 HPV-type specific titers
for the 48 months of follow up (Table 3a, Fig. 3a and b) compared
to children with detectable HIV viral load (P < 0.001). There was,
however, no difference in the rate of HPV antibody response
decline over time by plasma HIV RNA status (Table 3b).

Fig 2b. Log10 HPV Antibody Titers (HPV-16 and HPV-18) Over 48 Months Post Vaccination.

Table 3a
Association between HIV-1 plasma viral load and HPV antibody response over time.

Log10 HPV-6 Log10 HPV-11 Log10 HPV-16 Log10 HPV-18

Effect HIV viral load status Estimate p-value Estimate p-value Estimate p-value Estimate p-value
(95% CI) (95% CI) (95% CI) (95% CI)
Intercept Undetectable 2.28 <0.0001 2.17 <0.0001 3.01 <0.0001 2.25 <0.0001
(2.12, 2.44) (2.00, 2.34) (2.81, 3.21) (2.04, 2.47)
Detectable 1.74 <0.0001 1.58 <0.0001 2.27 <0.0001 1.44 <0.0001
(1.58, 1.91) (1.41, 1.76) (2.07, 2.47) (1.22, 1.66)
Time Undetectable 0.0097 <0.0001 0.0107 <0.0001 0.0109 <0.0001 0.0116 <0.0001
(-0.0128, 0.0067) (-0.0139, 0.0075) (-0.0145, 0.0072) (-0.0155, 0.0077)
Detectable 0.0095 <0.0001 0.0120 <0.0001 0.0119 <0.0001 0.0104 <0.0001
(-0.0127, 0.0064) (-0.0153, 0.0086) (-0.0157, 0.0081) (-0.0145, 0.0063)

5
N. Mugo, L.O. Eckert, L. Odero et al. Vaccine xxx (xxxx) xxx

Table 3b HPV-16 seropositivity remained at 100% while HPV-6, -11 and -18
Difference in time effect (the rate of decline) between undetectable and detectable seropositivity rates were 71–85%. Across studies, HIV viral load and
HIV viral load groups.
CD4 count correlated strongly with HPV seroconversion and geo-
HPV type Difference 95% CI p-value metric mean titer of HPV antibodies [28,34]. In our initial assess-
(Undetectable – Detectable) ment, at month 7 and 12 of follow up [28], we found an
Log10 HPV-6 0.0002 0.0046, 0.0041 0.92 association of plasma HIV RNA and CD4 count at vaccination with
Log10 HPV-11 0.0012 0.0034, 0.0059 0.60 HPV titers; this finding was confirmed on extended follow-up. The
Log10 HPV-16 0.0001 0.0043, 0.0063 0.71
Log10 HPV-18 0.0012 0.0068, 0.0045 0.69
evolution of HPV titers correlated with baseline HIV RNA, and chil-
dren with detectable viral load were less likely to sustain HPV
seropositivity over 48 months of follow up.
Natural HPV infection is limited to intraepithelial layer of the
cervix and the virus is shed from the mucosal surface inducing lit-
4. Discussion tle or no viremia which likely restricts the immune response. In
addition, HPV infection does not induce an inflammatory reaction.
Our study results demonstrate that HPV antibody seropositivity The HPV vaccines are composed of virus-like particles (VLP) made
for the majority of this cohort of adolescents living with HIV vacci- for the L1 major capsid protein of specific HPV sero-types and
nated with three doses of the QHPV remained above the cut off induce an immune response several fold greater than natural infec-
threshold 48 months post initial vaccination and is comparable tion. The vaccine VLPs delivered intramuscularly induce local
to same age cohort of HIV-1 uninfected children from the primary inflammation and activate the adaptive immune response which
clinical trials conducted in Europe [31]. HIV infected children with culminates in a memory pool of B-memory cells that provide
detectable HIV viral load at the time of HPV vaccination were less long-term protection [35]. While antibody titers wane over time,
likely to sustain a vigorous antibody response to HPV. The pattern plasma cells with low but constant production are retained;
of decline mimics the same pattern observed among HIV-infected antigen-specific circulating memory cells also can be found after
and uninfected vaccinated girls and women [32] from other set- vaccination [35]. It is possible that the few children who did not
tings, with a plateau after month 24 [33]. The sustained HPV retain immune response over time would benefit from a booster
seropositivity and GMT levels gives reassurance of possible long- vaccine dose. Alternatively, exposure to wild-type HPV may elicit
term efficacy of vaccination and sustained protection from HPV- an anamnestic response, similar to response observed in hepatitis
related morbidities. B immunized persons whose antibody titers have waned [36,37].
Limited data are available on long-term persistence of HPV anti- Longitudinal follow up of cohorts of HIV-uninfected girls and
body among persons living with HIV. Levin et al. [25] followed up a young women show sustained effectiveness in presence of low
cohort of 30 children in the USA who received a standard 3-dose GMT titers providing some reassurance. For example, among
regimen. At year 3, among 14 participants who provided samples, young girls and women enrolled in the FUTURES study cohort,

Fig 3. Log10 HPV Antibody Titers by HIV RNA Over 48 Months Post Vaccination.

6
N. Mugo, L.O. Eckert, L. Odero et al.
who completed three doses of QHPV vaccination and were both
HPV seronegative and PCR negative at the initial vaccination dose,
the anti-HPV 18 GMT seropositivity rate at month 44 measured
using cLIA was 60.3%, with GMT of 33.8 mMU/mL (95% CI 32.0–
35.7). However, the vaccine efficacy against any grade CIN or Ade-
nocarcinoma in Situ (AIS) related to HPV-18 was 98.4% (95% CI:
90.5–100.0) [38], with only one HPV-18 related lesion compared
to 60 among the placebo arm participants, demonstrating protec-
tion against HPV acquisition even with low anti-HPV antibody
titers.
To date, the HPV antibody threshold that correlates with protec-
tion from HPV infection and HPV-associated precancerous lesions
and cancer has not been established. Ultimately, persistent protec-
tion from HPV infection and related infections can only be ascer-
tained by longer term follow up and assessment for HPV
infection and intraepithelial lesions. The high rates of seropositiv-
ity in this cohort is reassuring, however, it would be beneficial to
ascertain protection with assessment for HPV infection or intraep-
ithelial lesions. Schiller et al has demonstrated in mice that HPV
neutralization occurs at the picomolar level which is below our
ability to measure [39] further emphasizing the value of ascertain-
ing HPV vaccine long term effectiveness among HIV-1 infected
children.
Our study found HPV seropositivity rates and durability among
HIV-infected adolescent girls and boys in Kenya to be lower than
observed in studies done outside of the Africa continent, but the
majority remained above standard cut off threshold for seroposi-
tivity. The duration of protective immunity remains an important
question, as women (and men) remain at risk for HPV infection
and related diseases as long as they are sexually active. Addition-
ally, populations of HIV infected persons with sub-optimal HIV
viral suppression are at increased risk of HPV associated morbidi-
ties and need effective protection against HPV infections. To for-
mulate definitive guidelines for HIV-infected children, the field
requires more data with HPV infection and cervical intraepithelial
lesions as outcomes to demonstrate long-term vaccine effective-
ness in this population. The current CDC guidelines recommend 3
doses of HPV vaccine for HIV-infected individuals ages 9–26 years,
and our findings support a similar schedule for African HIV-
infected children. There is, however, still a gap in knowledge, on
the efficacy of reduced HPV dose schedule among HIV-infected
children.
Funding
This study was supported in part by a research grant from
Investigator-Initiated Studies Program of Merck Sharp & Dohme
Corp and received by Nelly Mugo (MISP) IISP 51802. The opinions
expressed in this paper are those of the authors and do not neces-
sarily represent those of Merck Sharp & Dohme Corp.
Declaration of Competing Interest
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: Nelly Mugo reports receiving funds from Merck Inc. to
conduct the study referenced through an investigator-initated
study grant (MISP). Anna Wald has participated in a DSMB for a
Merck sponsored clinical trial and received study products from
Merck for an NIH-sponsored study.
Jared Baeten has served on advisory boards for Gilead Sciences,
Janssen, and Merck.
7
Vaccine xxx (xxxx) xxx
Acknowledgement
The authors greatly acknowledge the invaluable contributions
and commitment of the children and their parents/guardians for
their contribution in time, adherence to study procedures and high
retention to study visits. This work would not have been feasible
without the contributions of the Partners in Health Research and
Development (PHRD) study team notably Dr. Murugi Micheni, Jac-
inta Nyokabi, and Peter Mogere.
References
[1] Ll V. human papillomavirus types 6/11/16/18 L1 virus like particle vaccine
through 5 years of follow-up. Br J Cancer 2006.
[2] Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted
bivalent L1 virus-like-particle vaccine against infection with human
papillomavirus types 16 and 18 in young women: an interim analysis of a
phase III double-blind, randomised controlled trial. Lancet 2007;369
(9580):2161–70.
[3] Stanley M, Lowy DR, Frazer I. Chapter 12: Prophylactic HPV vaccines:
underlying mechanisms. Vaccine. 2006;24 Suppl 3:S3/106–113.
[4] Munoz N, Kjaer SK, Sigurdsson K, et al. Impact of human papillomavirus (HPV)-
6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J
Natl Cancer Inst 2010;102(5):325–39.
[5] Lang Kuhs KA, Gonzalez P, Rodriguez AC, et al. Reduced prevalence of vulvar
HPV16/18 infection among women who received the HPV16/18 bivalent
vaccine: a nested analysis within the Costa Rica Vaccine Trial. J Infect Dis
2014;210(12):1890–9.
[6] Apter D, Wheeler CM, Paavonen J, et al. Efficacy of human papillomavirus 16
and 18 (HPV-16/18) AS04-adjuvanted vaccine against cervical infection and
precancer in young women: final event-driven analysis of the randomized,
double-blind PATRICIA trial. Clin Vaccine Immunol 2015;22(4):361–73.
[7] Cameron RL, Kavanagh K, Cameron Watt D, et al. The impact of bivalent HPV
vaccine on cervical intraepithelial neoplasia by deprivation in Scotland:
reducing the gap. J Epidemiol Community Health 2017;71(10):954–60.
[8] Machalek DA, Garland SM, Brotherton JML, et al. Very low prevalence of
vaccine human papillomavirus types among 18- to 35-year old australian
women 9 years following implementation of vaccination. J Infect Dis 2018;217
(10):1590–600.
[9] Drolet M, Benard E, Perez N, Brisson M, Group HPVVIS. Population-level impact
and herd effects following the introduction of human papillomavirus
vaccination programmes: updated systematic review and meta-analysis.
Lancet 2019.
[10] Goodman T. Update on HPV vaccine introductioin and programmatic
perspectives. World Health Organization. https://www.who.int/
immunization/sage/meetings/2018/october/SAGE_october_2018_HPV_
Goodman.pdf. Published 2018. Accessed.
[11] De Vuyst H, Mugo NR, Chung MH, et al. Prevalence and determinants of human
papillomavirus infection and cervical lesions in HIV-positive women in Kenya.
Br J Cancer 2012;107(9):1624–30.
[12] Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in
people with HIV/AIDS compared with immunosuppressed transplant
recipients: a meta-analysis. Lancet 2007;370(9581):59–67.
[13] Ellerbrock TV, Chiasson MA, Bush TJ, et al. Incidence of cervical squamous
intraepithelial lesions in HIV-infected women. JAMA 2000;283(8):1031–7.
[14] Rowhani-Rahbar A, Hawes SE, Sow PS, et al. The impact of HIV status and type
on the clearance of human papillomavirus infection among Senegalese
women. J Infect Dis 2007;196(6):887–94.
[15] Massad LS, Xie X, Burk R, et al. Long-term cumulative detection of human
papillomavirus among HIV seropositive women. AIDS 2014;28(17):2601–8.
[16] Denny LA, Franceschi S, de Sanjose S, Heard I, Moscicki AB, Palefsky J. Human
papillomavirus, human immunodeficiency virus and immunosuppression.
Vaccine 2012;30(Suppl 5):F168–74.
[17] Kojic EM, Cu-Uvin S, Conley L, et al. Human papillomavirus infection and
cytologic abnormalities of the anus and cervix among HIV-infected women in
the study to understand the natural history of HIV/AIDS in the era of effective
therapy (the SUN study). Sex Transm Dis 2011;38(4):253–9.
[18] Massad LS, Seaberg EC, Watts DH, et al. Long-term incidence of cervical cancer
in women with human immunodeficiency virus. Cancer 2009;115(3):524–30.
[19] Kelly H, Weiss HA, Benavente Y, et al. Association of antiretroviral therapy
with high-risk human papillomavirus, cervical intraepithelial neoplasia, and
invasive cervical cancer in women living with HIV: a systematic review and
meta-analysis. Lancet HIV 2018;5(1):e45–58.
[20] Lehtinen M, Lagheden C, Luostarinen T, et al. Ten-year follow-up of human
papillomavirus vaccine efficacy against the most stringent cervical neoplasia
end-point-registry-based follow-up of three cohorts from randomized trials.
BMJ Open 2017;7(8):e015867.
[21] Ault KA, Future IISG. Effect of prophylactic human papillomavirus L1 virus-
like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade
N. Mugo, L.O. Eckert, L. Odero et al.
3, and adenocarcinoma in situ: a combined analysis of four randomised
clinical trials. Lancet 2007;369(9576):1861–8.
[22] Arbyn M, Xu L. Efficacy and safety of prophylactic HPV vaccines. A Cochrane
review of randomized trials. Expert Rev Vaccines 2018;17(12):1085–91.
[23] Huh WK, Joura EA, Giuliano AR, et al. Final efficacy, immunogenicity, and
safety analyses of a nine-valent human papillomavirus vaccine in women aged
16–26 years: a randomised, double-blind trial. Lancet 2017;390
(10108):2143–59.
[24] Levin MJ, Moscicki AB, Song LY, et al. Safety and immunogenicity of a
quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-
infected children 7 to 12 years old. J Acquir Immune Defic Syndr 2010;55
(2):197–204.
[25] Levin MJ, Huang S, Moscicki AB, et al. Four-year persistence of type-specific
immunity after quadrivalent human papillomavirus vaccination in HIV-
infected children: Effect of a fourth dose of vaccine. Vaccine 2017;35
(13):1712–20.
[26] Kojic EM, Kang M, Cespedes MS, et al. Immunogenicity and safety of the
quadrivalent human papillomavirus vaccine in HIV-1-infected women. Clin
Infect Dis 2014;59(1):127–35.
[27] Kahn JA, Xu J, Kapogiannis BG, et al. Immunogenicity and safety of the human
papillomavirus 6, 11, 16, 18 vaccine in HIV-infected young women. Clin Infect
Dis 2013;57(5):735–44.
[28] Mugo NR, Eckert L, Magaret AS, et al. Quadrivalent HPV vaccine in HIV-1-
infected early adolescent girls and boys in Kenya: Month 7 and 12 post vaccine
immunogenicity and correlation with immune status. Vaccine 2018;36
(46):7025–32.
[29] Dias D, Van Doren J, Schlottmann S, et al. Optimization and validation of a
multiplexed luminex assay to quantify antibodies to neutralizing epitopes on
human papillomaviruses 6, 11, 16, and 18. Clin Diagn Lab Immunol 2005;12
(8):959–69.
[30] Pacheco-Dominguez RL, Durazo-Arvizu RA, Lopez-Hernandez A, Figueroa-
Padilla J, Ramirez-Gonzalez JB, Lopez-Cervantes M. Seroprevalence of HPV
Vaccine xxx (xxxx) xxx
serotypes 6, 11, 16 and 18 in unvaccinated children from Mexico City.
Epidemiol Infect 2019;147:e257.
[31] Merck & Co. I. GARDASIL product information. https://www.fda.gov/media/
74350/download Web site. Published In: Merck & Co. WS, NJ, editor.
Whitehouse Station (NJ): Merck & Co.; 2009. Accessed.
[32] Brown DR, Garland SM, Ferris DG, et al. The humoral response to Gardasil over
four years as defined by total IgG and competitive Luminex immunoassay.
Human Vaccines 2011;7(2):230–8.
[33] Olsson SE, Villa LL, Costa RL, et al. Induction of immune memory following
administration of a prophylactic quadrivalent human papillomavirus (HPV)
types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine 2007;25
(26):4931–9.
[34] Moscicki AB, Karalius B, Tassiopoulos K, et al. Human papillomavirus antibody
levels and quadrivalent vaccine clinical effectiveness in perinatally human
immunodeficiency virus-infected and exposed, uninfected youth. Clin Infect
Dis 2019.
[35] Stanley M. Potential mechanisms for HPV vaccine-induced long-term
protection. Gynecol Oncol 2010;118(1 Suppl):S2–7.
[36] Bagheri-Jamebozorgi M, Keshavarz J, Nemati M, et al. The persistence of anti-
HBs antibody and anamnestic response 20 years after primary vaccination
with recombinant hepatitis B vaccine at infancy. Hum Vaccin Immunother
2014;10(12):3731–6.
[37] West DJ, Calandra GB. Vaccine induced immunologic memory for hepatitis B
surface antigen: implications for policy on booster vaccination. Vaccine
1996;14(11):1019–27.
[38] Joura EA, Kjaer SK, Wheeler CM, et al. HPV antibody levels and clinical efficacy
following administration of a prophylactic quadrivalent HPV vaccine. Vaccine
2008;26(52):6844–51.
[39] Longet S, Schiller JT, Bobst M, Jichlinski P, Nardelli-Haefliger D. A murine
genital-challenge model is a sensitive measure of protective antibodies against
human papillomavirus infection. J Virol 2011;85(24):13253–9.