Prospective Longitudinal Study on Immunogenicity, Induction of Cellular Immune Responses and Safety of Vaccination Against HPV With the 9-valent Vaccine in HIV-positive Women (The Papillon Study)
Phase: PHASE4
Conditions: HPV - Anogenital Human Papilloma Virus Infection, HIV Infections
Sponsor: Centre Hospitalier Universitaire Saint Pierre

1 
 
Prospective longitudinal study on immunogenicity, induction of 
cellular immune responses and safety of vaccination against HPV 
with the 9valent vaccine in HIV-positive women 
The Papillon study 
 
French title: 
Etude longitudinale et prospective sur l’immunogénicité, l’induction 
d’immunité cellulaire et la sécurité de la vaccination contre le HPV par 
le vaccin 9valent chez les femmes VIH-positives  
Etude Papillon 
 
Phase IV prospective study evaluating the reactogenicity and immunogenicity (both humoral 
and cellular responses) and the safety of the 9valent vaccine against HPV 
(Gardasil9®Merck) in HIV-positive women aged 15-40 years with fully suppressed HIV 
viremia on combined antiretroviral therapy. After a first open phase evaluating tolerability of 
Gardasil9, women will be randomized between two different doses schedules: in the first 
schedule,  women will receive  2 doses  at time 0 and 6 months and a third dose between  
18-48 months if their antibody levels are insufficient; the second schedule will be 3 doses at  
0, 2 and 6 months. Primary outcome is the non-inferiority of the rate of seroconversion 
against each HPV vaccine genotypes in women seronegative at baseline after either 2 or 3 
doses of vaccination (month 7). Secondary outcomes are rate of seroconversion after 3 
doses if they have received a third dose, completion of vaccine schedule, vaccine safety, 
antibody titles, and induction of cellular immunity against HPV contained in the vaccine, 
incidence of cervical HPV infection and incidence of abnormal cytology after vaccination. 
Date:  
  
15/12/2023 
Author:  
 
Dr Deborah Konopnicki and Prof De Wit Stéphane 
Version:  
 
7 
NCT 
 
 
NCT03391921 
EUDRACT 
 
2018-000228-33 
FAMHP:  
 
FADG/R&D/BEN/mmn 
 
 
 

2 
 
Prospective longitudinal study on immunogenicity, 
induction of cellular immune responses and safety of 
vaccination against HPV with the 9valent vaccine in HIV-
positive women 
The Papillon study 
 
Executive summary 
Design 
Phase IV prospective randomized  study comparing  the reactogenicity and  the 
immunogenicity (neutralizing antibody titles against each HPV vaccine genotype) of the 
9valent vaccine against HPV (Gardasil9®Merck) in HIV-positive women aged 15-40 years 
with fully suppressed HIV viremia on combined antiretroviral therapy receiving two different 
vaccination schedules: 0, 2 and 6 months or 0, 6 months and a third later booster if needed. 
The safety of the vaccination (local or systemic reaction and impact on HIV viral control and 
immunodeficiency level) will be assessed.                                                                              
The cellular immune response will be assessed in a subgroup of patients. 
Inclusion criteria 
 
HIV-positive woman 
 
Age 15-40 years 
 
Undetectable HIV viral load (VL) <400 cp/ml) for at least 6 months (i,e: having at 
least two separate VL<400 cp/ml at 6 months intervals; the most recent VL <400 
cp/ml may be the screening CV for the study). 
 
No planned pregnancy foreseen for the next 7 first months and use of contraception 
such as condom, hormonal contraception or intrauterine device 
 
IC signed 
 
Exclusion criteria 
 
Previous hysterectomy or conisation 
 
Previous or current biopsy-proven cervical, vulvar or vaginal HPV-associated lesion 
defined as ≥CIN2, VIN2, VaIN2 or invasive carcinoma  
 
Previous vaccination against HPV (at least one dose) 
 
Ongoing or planned pregnancy foreseen in the next 7 months 
 
Other immunodeficiency conditions such as ongoing or previous (within 6 months) 
chemotherapy against cancer or chronic systemic corticosteroids treatment or 
immunosuppressive therapy after transplantation 
 
Any condition contraindicating intramuscular injection such as warfarin therapy. 

3 
 
 
Number of patients 
Study: 200 patients 
First phase: open label: 3 doses of vaccine at 0, 2 and 6 months 
Second phase (150 patients): randomized  study comparing two arms: 
 ARM A schedule of vaccination (75 patients): 0 and 6 months and  a facultative later 
booster dose  if antibodies level insufficient at month 7  
 
 ARM B schedule of vaccination(75 patients): 0,2 and 6 months  
Substudy on  cellular immune responses  in a subset of patients: 40 patients and separated 
informed consent 
Amendment (February 2021) : Introduction of a third phase of the study 
At the time of the start of the Papillon study (June 2018), there was no experience 
nor publication of vaccination with Gardasil9 in women living with HIV (WLHIV). 
We have then started our study by a first open label part including 45 patients to  
observe if tolerance and safety was equal to what was described in HIV-negative 
women. At the end of this open label part (from June 2018 to January 2019), our 
data on safety were reassuring and we proceeded to the randomized phase as 
described upper (from January 2019 to February 2021).  
Because of the SARS-CoV2 pandemic, the enrollment had been slowed down and 
by February 2021, we had randomized 102 WLHIV instead of 150. 
As we needed to end the study enrolment by September 2019 because of budget 
constraints, we have introduced an amendment to give two doses (as in ARM A) to 
all the patients enrolled from February 25th 2021. 
We plan to analyze the results in intention-to-treat on the randomized cohort  
(n=102), and in On-treatment on the whole cohort (n=169). 
 
Amendment (December  2023) : 
In order to investigate the role of basal immune activation on the seroconversion 
and long-term persistence of HPV-specific antibody responses, we wish to extend 
the follow up to the following time points : 
- 
24 months 
- 
36 months 
- 
48 months 
- 
60 months 

4 
 
After completion of the vaccine administration  (2 or 3 doses). 
Women included will  be contacted in order to collect a serum sample and will sign 
a new informed consent. If the time point is exceeded, we will retrieved plasma 
samples collected during routine care for HIV viral load determination (stored at 
the AIDS Reference Laboratory-LHUB ULB). 
  
Primary outcome 
Rate of seroconversion of neutralizing antibodies against each HPV vaccine genotypes 
namely 6/11/16/18/31/33/45/52/58 among women seronegative at baseline for HPV 
vaccine genotypes, by measuring neutralizing antibody against the 9 vaccine genotypes of 
HPV at baseline, month 7. Comparison of that rate at month 7 (non inferiority defined as at 
least 80% of seroconversion in ARM A). 
 
Secondary outcomes 
 
Completion of vaccine schedule. 
 
Safety and clinical tolerance of the vaccine administration. 
 
Impact on T-lymphocytes CD4+ counts and HIV viremia at month 7. 
 
Rate of seroconversion of neutralizing antibodies against each HPV vaccine genotypes 
namely 6/11/16/18/31/33/45/52/58 among women seronegative at baseline for HPV 
vaccine genotypes, by measuring neutralizing antibody against the 9 vaccine 
genotypes of HPV at Month 18, 24, 36, 48 and 60 compared to baseline. 
 
Measure of neutralizing antibodies title against each HPV vaccine types at baseline, 
month 7 and 18 
 
Assessment of long term persistence of HPV-specific antibody responses at 24,36,48 
and 60 months after completion of the last vaccine administration dose.  
 
The cellular immune response against HPV 16/18/31/52/58 will be assessed in a 
subgroup of patients (n=40, 20 in each arm) on PBMC samples tested. For this 
analysis, a separated IC should be first signed by the patient. 
 
Incidence and prevalence of HPV infections and of abnormal cervical cytology 
performed by cytology and PCR on cervical swab at baseline and 12 months after the 
end of vaccination. 

5 
 
List of abbreviation 
ACIP   
 
Advisory Committee on immunization Practices cART 
cART  
 
combined antiretroviral therapy 
CIN  
 
Cervical Intraepithelial Neoplasia 
HR 
 
 
high risk 
HRHPV 
 
high risk HPV 
HG 
 
 
high grade 
HGCIN 
 
high grade cervical intraepithelial neoplasia 
HGVAIN 
 
high grade vaginal intraepithelial neoplasia 
HGVIN 
 
high grade vulvar intraepithelial neoplasia 
HIV  
 
human immunodeficiency virus 
HPV  
 
human papillomavirus 
IC 
 
 
informed consent 
ICC 
 
 
invasive cervical cancer 
NCI  
 
National Cancer Institute 
PBMC  
 
peripheral blood mononuclear cell 
VaIN  
 
Vaginal Intraepithelial neoplasia 
VIN  
 
Vulvar Intraepithelial neoplasia 
VLP   
 
Virus-like particle  
 
 
 
 

6 
 
 
Rationale 
 
In women, persistent infection with high risk (HR) Human papillomavirus (HPV) is 
responsible for the development of high grade cervical, vulvar or vaginal 
intraepithelial neoplasia (HGCIN, HGVIN, HGVAIN) and invasive cervical cancer 
(ICC). Worldwide, HPV 16 and 18 represent respectively 50 and 20% of all HRHPV 
genotypes responsible for ICC [1]. Prophylactic vaccination against HPV 16 and 18 
in adolescent and young women aged 16-26 years has been shown to be highly 
efficient in preventing both infection with these genotypes of HRHPV and HPV-
associated lesions such as HGCIN, HGVIN, HGVAIN due to vaccine types (prevention 
of >90%) [2-4]. Vaccination of women aged 26-45 years is also efficient with 
around 80% of prevention for both infections and lesions related to vaccine HPV 
types [5-6].  
 
HIV-positive women are more frequently infected with persistent HRHPV and suffer 
significantly more from HPV-associated diseases such as ICC (6 to 10 times more 
frequent than in the general population) and precancerous lesions. Their dysplastic 
lesions are more severe and they have a worst outcome after treatment [7-8]. 
 
We have conducted a prospective longitudinal study on HRHPV infection and HPV-
associated diseases in a cohort of almost 900 HIV-positive women living in Belgium. 
We found that HRHPV infection was highly prevalent (43%) with a high incidence of 
new infections (13/100 women-year) [9-10]; 28% had cervical intraepithelial 
abnormal cytology and 3% had HGCIN compared to respectively 6% and 1.2% in 
the general Belgian population. We also showed that the most prevalent HPV 
genotypes were HPV 52 (20%), HPV 18 (15%), HPV 31/35/51/58 (12% each) and 
HPV 16% (9.5%)[11]. This genotypic distribution is different from the general 
population and is attributable first to HIV-infection which is a known risk factor for 
more frequent infection with HPV other than 16 or 18 and second with the African 
origin of most women followed for HIV in Belgium (similar genotype distribution is 
found in women living in sub-Saharan African countries).  
 

7 
 
Immunogenicity of the prophylactic vaccines against HPV 16 and 18 has been 
evaluated in several studies including almost 700 HIV-positive female between 8 
and 45 years [12-17].  Most studies were done with the quadrivalent vaccine 
against HPV 6/11/16/18 (Gardasil®Merck). These studies showed a high 
seroconversion rate >90% for all HPV vaccine types in particular in patients with 
high CD4 cell count or under combined antiretroviral therapy (cART). These studies 
showed also that the presence of antibodies (seropositivity) against all vaccine-
types HPV before vaccination was present in only 4-5% of women (median age 21 
and 36 years) which suggest that in most HIV-positive adult women, there could be 
a benefit to vaccinate and protect against the HPV genotypes not yet encountered 
[14, 16]. Moreover, in patients seropositive for one or several HPV vaccine 
genotype(s), vaccination was able to induce a significant increase in these antibody 
titles (by 1.5 log10 mMU/ml) [17]. 
 
The ideal timing for vaccination against HPV is during adolescence however most 
adult women followed for HIV today had no opportunity to receive these vaccines 
during adolescence. The ACIP (Advisory Committee on immunization Practices), the 
British HIV Association and the Belgian Superior Health Council are recommending 
to vaccinate adult HIV-positive women against HPV [18, 19, 20]. This is partially 
based on the excellent results of the registration studies for the three different 
vaccines which demonstrated high efficacy in women up to 26 years. It is also 
based on later studies performed in HIV-negative women between 24 and  45 years 
old which demonstrate very good efficacy (between 88 and 91%) in the prevention 
of  a combined endpoint (including persistent HRHPV infection, which is the 
preceding stage before precancerous lesions, external lesions such as genital warts 
and CIN1 due to HPV vaccinal types) [4-5]. 
 In the USA, the ACIP recommends vaccinating HIV-positive patients against HPV as 
soon as possible starting from 11 and up to 26 and in the UK up to 40 years.  
 
In Belgium, there are currently three available vaccines against HPV:  the bivalent 
vaccine against HPV 16 and 18 (Cervarix®GSK), the quadrivalent vaccine against 

8 
 
HPV 6/11/16/18 (Gardasil®Merck) and the new ninevalent vaccine against HPV 
6/11/16/18/31/33/45/52/58 (Gardasil9®Merck) available since June 2016. 
They are reimbursed in girls aged 12-18 years but are very expensive for women of 
19 years or more: a course of 3 doses costs between 207 (Cervarix), 355 (Gardasil) 
and 404 euros (Gardasil9) (prices on October 19th 2017). 
 
We have shown that the bi- or quadrivalent vaccines would cover at best 30% of 
our patients because they are infected with HPV genotypes other than 16 and 18; in 
comparison, vaccinating with the ninevalent vaccine would cover up to 82% of these 
women because it includes 5 additional HRHPV genotypes more frequently retrieved 
in our patients [11] . Other authors have shown similar results either in CIN3 from 
HIV-positive women or in AIN3 in HIV-positive man from the USA [21-22]. 
 
No data on the immunogenicity or safety of the ninevalent vaccine in HIV-positive 
patients are available so far. As the HRHPV genotypes included in this vaccine could 
better cover our patients than the bi- or quadrivalent vaccines, studying the 
immunogenicity and the safety of this vaccine in HIV-positive women is thus 
essential.  
 
Regarding safety, an analysis of seven trials over 15,000 individuals who received at 
least one dose of the ninevalent vaccine, showed that the most common adverse 
effects were mild or moderate injection site reactions (pain, erythema, and 
swelling), occurring slightly more frequently than with the quadrivalent vaccine. The 
frequency of systemic adverse effects (eg, headache, fever, nausea, dizziness) was 
similar to the quadrivalent vaccine. Serious adverse effects occurred in <0.1 percent 
[23,24]. 
 
Our objective is to provide data on the immunogenicity and safety of the ninevalent 
vaccine which has not yet been reported for HIV-positive women although they are 
at greater risk of HRHPV infection and associated cancerous diseases. Our results 
could impact not only on the management of the 5700 women living with HIV in 
Belgium [25] but also on the healthcare of millions across the world who still suffer 

9 
 
from an unacceptable rate of HPV-related cancer and precancerous lesions. In sub-
Saharan Africa, ICC is the first most frequent cancers in HIV-positive young women 
(30-40 years) with an incidence of up to 450/100.000 women-year compared to 30-
50 in Africa and 9 /100.000 women-year in Belgium, both in the general population 
[26]. 
 
We also aim to provide data on cellular immune response against HRHPV in HIV-
positive women. Several studies in HIV positive patients have shown that HPV 
vaccination was able to increase the specific cellular immune responses against HPV 
such as a raise in CD4+  and CD8+ lymphocytes against HPV 16 and 18 [13, 15]. 
This analysis comparing the evolution between cellular immune response targeted 
to specific HRHPV genotypes before and after vaccination will be performed in a 
subset of 40 patients and will focus on the vaccine genotypes most frequently 
encountered in our cohort such as 16/18/31/52 and 58.  
 
 
By December 2018, many questions have aroused about how many doses of 
vaccine against HPV should be given to be efficient. The registration studies for 
Cervarix and Gardasil were performed in the early 2000’ with a three doses 
schedule (0, 1 or 2 and 6 months) based on previous studies with similar protein-
based vaccine such as hepatitis B vaccine. However, all the vaccines against HPV 
are designed as virus-like particle (VLP) with unique immunogenic properties.  
Immunobridging studies have confirmed that a twodoses regimen (0 and 6 months) 
was as reactogenic (giving an antibody response in >95% of the vaccinated 
subjects that were seronegative at baseline) and as immunogenic (inducing an 
antibody response of the same magnitude) as a three-dose schedule in teenagers 
less than 15 years –old [27]. More recently several randomized-controlled studies 
have shown that one- versus two- versus three-doses schedule were equivalent in 
terms of clinical endpoint. The Costa Rica Vaccine Trial (CVT) and the Papilloma 
TRIal against Cancer In young Adults (PATRICIA Trial), both studies using bivalent 
vaccine, showed similar vaccine efficacy over four years among women who 
received one, two and three doses of the HPV16/18 vaccine, and stable antibody 

10 
 
responses have been observed throughout the seven years of follow-up accrued to 
date in CVT, suggesting durability of responses [28].  Additionally, 36-month 
preliminary analysis of a large, post-licensure trial of the quadrivalent vaccine in 
India showed similar protection against HPV16/18 cervical infection whether the 
women received one dose, two doses, or three doses [29]. However, vaccine 
recipients in these trials were not randomized to receive these fewer doses, and 
immunogenicity among one-dose recipients was lower than that observed following 
two- or three-doses, leading regulatory bodies to conclude that the level of evidence 
in support of single-dose HPV vaccination is insufficient to warrant changes in 
current recommendations for two- or three- dose schedules. Consequently, the 
American National Cancer Institute (NCI) has recently launched a large randomized 
study comparing the clinical efficacy of Cervarix in one or two doses to Gardasil9 in 
one or two doses.  
 
Indeed, the possibility of giving less than three doses is important in terms of 
compliance to the full vaccination scheme, tolerability of the vaccine and last but 
not least in terms of costs which are important with these vaccines. In Belgium, 
these vaccines are not reimbursed after 18 years-old even in more fragile 
population such as HIV-positive persons and total cost for a three-dose vaccine is 
more than 400 Euros.  
 
Up to now, there is no data for less than three doses in HIV-positive women or HIV-
positive adolescents and all the recommendations from the European AIDS clinical 
society, or British HIV Association or American guidelines on HIV and on vaccination 
recommend a three doses schedules for HIV adolescent or adults. 
 
In order to answer the question of whether a two-doses schedule is not inferior to a 
three-doses schedule in HIV-positive women, we propose to randomly evaluate the 
reactogenicity and the immunogenicity of 2 different vaccination schedules given 
according to randomization in HIV virally-suppressed women under cART: Arm A 
would receive vaccination with 9valent vaccine at time 0 and at month 6 and a later 
facultative booster if antibodies measurement at month 7 are insufficient. Arm B 

11 
 
would receive 9valent vaccine at 0, 2 and 6 months. We will measure the antibody 
responses in both arms at baseline and month 7 (one month after the second or the 
third dose) to determine if a good antibody response can be reached already after 2 
doses or needs a third dose in ARM A.  
 
Our study has started as a phase IV open study enrolling patients in March 2018 
and vaccinating the first patient in June 2018: up to now, 42 women have received 
the first dose of the three-doses schedule (0,2 and 6) and 25 have also received the 
second dose at month 2. The intermediate evaluation shows that acceptability and 
tolerability are excellent. We did not encounter adverse event of moderate or severe 
grade. 
We propose to continue the classical 3 doses schedule (0, 2 and 6 months) in the 
patients that have been already enrolled and to randomized all the new patients 
between ARM A and ARM B in order to continue our study as  a randomized non 
inferiority trial including 150 patients (75 per arm). 
 
Design of the study 
 
The study started as an open study to evaluate the reactogenicity, the 
immunogenicity and the cellular immune response against each HPV vaccine 
genotypes (6/11/16/18/31/33/45/52/58) at month 7 which will be one month after 
completion of a three doses schedule (0, 2 and 6 months) in women seronegative at 
baseline for these antibodies. 
 
After the December 2018 amendment, the study will enter a second phase as a 
non-inferiority study with  randomization between two arms: 
 
 ARM A: vaccination at time 0 and 6 month and a later facultative 
booster if needed according to month 7 antibodies measurement 
 
 ARM B: vaccination at time 0, 2 and  6 months 
 Amendment: Introduction of a third phase of the study 
 At the time of the start of the Papillon study (June 2018), there was no 
experience nor publication of vaccination with Gardasil9 in women living 

12 
 
with HIV (WLHIV). We have then started our study by a first open label part 
including 45 patients to  observe if tolerance and safety was equal to what 
was described in HIV-negative women. At the end of this open label part 
(from June 2018 to January 2019), our data on safety were reassuring and 
we proceeded to the randomized phase as described upper (from January 
2019 to February 2021).  
 Because of the SARS-CoV2 pandemic, the enrollment had been slowed down 
and by February 2021, we had randomized 102 WLHIV instead of 150. 
 As we needed to end the study enrolment by September 2019 because of 
budget constraints, we have introduced an amendment to give two doses 
(as in ARM A) to all the patients enrolled from February 25th 2021. 
 We plan to analyze the results in intention-to-treat on the randomized 
cohort  (n=102), and in On-treatment on the whole cohort (n=169). 
 
Antibodies title peaks one month after last vaccine dose than decrease to a plateau 
and stabilize around month 12 after receiving the last dose. In this study, antibodies 
against HPV will be measured at baseline, month 7 (that is to say 1 month after 
receiving 2 or 3 doses depending in which arm the patient has been randomized to) 
and month 18 (or 12 months after receiving the second or third dose, reflecting the 
stabilized antibodies level. We expect that two doses of vaccine in HIV-positive 
patients with well controlled HIV viremia under cART for at least 6 months could 
induce seroconversion in at least 80% of the patients seronegative at baseline 
whereas the seroconversion rate is expected to be 95% after 3 doses according to 
previous studies using the quadrivalent vaccine in HIV-positive patients. We find a 
minimum of 80% efficacy in the two doses arm acceptable as in this arm the 
vaccine costs would decrease by 33%, administration will be easier, the risk of local 
reaction after injection could also be decreased and compliance with the whole 
vaccine administration could be improved.  
 
Regarding the number of patients that should be enrolled in the study, we 
considered a sample size calculation based on the SAS 9.4 program for comparing 
two independent proportions (1:1 allocation in a non-inferiority trial) by a Pearson 
Chi-square test. If we consider 95% rate of seroconversion for ARM B (3 doses 
vaccines) and 80% for ARM A (2 doses vaccines) with a significance level test of 
0.05 (alpha) and an 80% statistical power (Beta), we found that 60 patients per 

13 
 
arm would be needed (120 patients in total). We would then need in total 150 
women to be randomized taking into account the possibility of follow-up lost. 
 
The purpose of vaccinating women is to induce antibody response against each HPV 
genotype contained in the vaccine and in particular against the 7 high-risk 
genotypes that induces cancer. If, after 2 doses of vaccine (ARM A), the month 7 
antibodies measure shows absence of seroconversion against one of the HPV 
genotypes contained in the vaccine, the participant will receive a third booster dose 
of Gardasil9. 
 
In order to assess long term persistence of HPV-specific antibody responses, the 
follow up will be prolonged to the following time points after completion of the 
vaccine administration  : 24, 36, 48 and 60 months. 
The role of basal immune activation on seroconversion rate and long terme 
persistence of antibody responses, will be assessed.  
 
 
Primary outcome 
 
The rate of seroconversion of specific neutralizing antibodies against each HPV 
vaccine genotypes (6/11/16/18/31/33/45/52/58) at month 7 (which will be one 
month after either two doses of vaccine in ARM A or completion of a three doses 
schedule (0, 2 and 6 months) in ARM B) in women seronegative at baseline for 
these antibodies. The measure will be performed on a 10 ml tube by cLIA technique 
in Merck laboratory (see material and methods) 30,31. Non inferiority of ARM A 
compared to ARM B will be reached if for each HPV genotype contained in the 
vaccine, at least 80% of the patients have a seroconversion rate.We will analyze 
the results in intention-to-treat on the randomized cohort  (n=102), and in On-
treatment on the whole cohort (n=169). 
 
 
Secondary outcomes  
 
1/Safety and tolerability of the vaccines will be evaluated by a specific questionnaire 
on a phone call made by the research team to the participant and scheduled at least 

14 
 
48 hours and maximum 7 days after each vaccine dose; the questionnaire will 
evaluate whether there is any complain regarding local reaction (pain, redness, 
swelling, pruritus), systemic reaction (fever, malaise and fatigue) or other side 
effect. In case of any usual complain > mild stage, or the presence of an unsual 
complain, the patient will be assessed by a visit and physical examination performed 
by the research team. The questionnaire has been elaborated according to the 
published data on safety evaluation of the ninevalent vaccine 24. 
 
2/The potential impact of vaccine administration on T-lymphocyte CD4+ cell count 
and HIV viremia will be assessed by measuring CD4 cell count and HIV viremia at 
baseline (any measure within 6 months before screening can be taken into account) 
and month 7. Any detectable HIVRNA >1000 cp/ml will be reassessed on a second 
samples taken 2-4 weeks later. Any significant decrease in T-lymphocyte CD4+ cell 
count (defined as a decrease by more of 5% in the percentage or >100 cells/µl) will 
be reassessed on a second sample taken 2-4 weeks later. 
 
3/ measure of the title of specific neutralizing antibodies against each HPV vaccine 
genotypes (6/11/16/18/31/33/45/52/58), at baseline, month 7 (i.e., 1 month after  
2 or 3 doses) by the cLIA technique and at month 18 ( 12 months after vaccination 
completion in 200 HIV-positive women by the IgG LIA technique [30].  
 
4/The cellular immune response will be evaluated in a subset of 40 patients, 20 per 
arm,  (aged 18-40 years old) by measuring specific CD4+T cells expressing CD40, 
IL2, IFN-g or TNF-alpha against HPV 16/18/31/52 and 58. The analysis will be 
performed on a PMBC sample of 30 to 50 ml taken at baseline and at month 7 (see 
Procedures for Collection and Handling of Study Specimens section); a separate IC 
has to be signed for this sub-analysis. 
 
4/ The incidence and prevalence rates of HPV infections and of abnormal cervical 
cytology performed by PCR and cytology will be done on cervical swab taken by the 
gynecologist at baseline and month 18. Cervical cytology and HPV infection will be 
assessed by the national reference centre for HPV (AML, Antwerpen) 32. The 

15 
 
baseline gynecological sample might have been taken up to 6 months before the 
vaccination. These swabs will be sampled in all participants with previous vaginal 
sexually activity. In case of no previous vaginal sexual intercourse, the samples will 
not be taken. 
 
5/Completion of the vaccine schedule 
Comparison of the proportion of women achieving full course of vaccine 
administration in each arm, namely for ARM A receiving 2 doses and for ARM B 
receiving 3 doses. 
 
6/ Proportion of patients needing a booster dose (i.e..a third dose) in ARM A 
If after 2 doses of vaccine (ARM A), the month 7 antibodies analysis shows absence 
of seroconversion against one of the HPV genotypes contained in the vaccine, the 
participant will receive a third booster dose. 
7/ Impact of basal immune activation (levels of CD25, sCD14, IP-10, IL-6, TNF-α, d-
Dimers, CRP) on the seroconversion rate and long term antibody persistance 
 
 
Randomisation 
We will generated a randomization schedule with the classical method of block 
randomization. In practice, fort this study with two arms, 75 patients each, we will 
decide a number of blocks of 25, with block size of 6. We will use SAS programming 
and SAS PROC PLAN for the generating randomization schedules (version 9.4 SAS 
institute, Cary North Carolina, USA). 
 
Amendment after Coronavirus crisis 
1.Due to the COVID-19 health crisis in Belgium including a lockdown between March 
15th 2020 and June 2020, some patients could not attend their scheduled 
appointments for this study. Moreover, the routine gynecological consultation was 
closed during the two-months lockdown. Now that the routine gynecological has 

16 
 
reopened,  it is busier than usual as patients that have missed their appointments 
need to be seen. The initial study protocol stated that the first vaccination dose 
should be performed within 6 months after the baseline cervical sample. In order 
not to repeat the baseline cervical sample in an already full consultation, we 
propose to extend this time lapse to 12 months.  
In the same way, we propose to extend the last serum and cervical samples delay 
to 18 months after the last vaccine dose (initially to be performed 12 months after 
last vaccination dose) so the 18-months visit can be postponed up to 24 months 
after first vaccination dose. 
2. Introduction of a third phase of the study 
At the time of the start of the Papillon study (June 2018), there was no experience 
nor publication of vaccination with Gardasil9 in women living with HIV (WLHIV). We 
have then started our study by a first open label part including 45 patients to  
observe if tolerance and safety was equal to what was described in HIV-negative 
women. At the end of this open label part (from June 2018 to January 2019), our 
data on safety were reassuring and we proceeded to the randomized phase as 
described upper (from January 2019 to February 2021).  
Because of the SARS-CoV2 pandemic, the enrollment had been slowed down and by 
February 2021, we had randomized 102 WLHIV instead of 150. 
As we needed to end the study enrolment by September 2019 because of budget 
constraints, we have introduced an amendment to give two doses (as in ARM A) to 
all the patients enrolled from February 25th 2021. 
We plan to analyze the results in intention-to-treat on the randomized cohort  
(n=102), and in On-treatment on the whole cohort (n=169). 
3. Extension of the study follow-up  
In order to assess long term persistence of antibody response, we will collect serum 
samples at different time points after completion of the vaccine schedule (24, 36, 
48 and 60 months.). If the time point is exceeded, plasma samples collected during 

17 
 
routine care will be retrieved for the AIDS reference laboratory (VUB-LHUB ULB). 
Signature of a new informed consent will be required before collecting stored or new 
samples.  
Inclusion criteria 
 
HIV-positive woman 
 
Age 15-40 years 
 
Undetectable HIV viral load (HIVRNA <400 cp/ml) for at least 6 months (i,e: 
having at least two separate VL<400 cp/ml at 6 months intervals; the most 
recent VL<400 cp/ml may be the screening CV for the study). 
 
No planned pregnancy  foreseen for the next 7 months and use of 
contraception such as condom, hormonal contraception or intrauterine device 
 
IC signed 
 
Exclusion criteria 
 
Previous hysterectomy or conisation 
 
Previous or current biopsy-proven cervical, vulvar or vaginal HPV-associated 
lesion defined as ≥CIN2, VIN2, VaIN2 or invasive carcinoma  
 
Previous vaccination against HPV (at least one dose) 
 
Ongoing or planned pregnancy foreseen in the next 7 months 
 
Other immunodeficiency conditions such as ongoing or previous (within 6 
months) chemotherapy against cancer or chronic systemic corticosteroids 
treatment or immunosuppressive therapy after transplantation 
 
Any condition contraindicating intramuscular injection such as warfarin 
therapy. 
 
Site of enrolment and study 
AIDS reference center in Saint-Pierre University hospital 
 
Ethical committee 
Saint-Pierre University hospital  
 
 
Informed consent 
All patients have to read and sign the inform(s) consent(s) before entering the 
study. 

18 
 
  
For participants aged 18 years or more, there is one IC to be red and signed before 
entering the main study. 
For participants aged less than 18 years old, there are two separated forms: one for 
the participant and one for her parents or legal representatives; these two forms 
have to be signed before entering the study. 
  
For persons participating to the sub-study on cellular immune response to the 
vaccine (they will be aged 18-40), there will be another separated IC to be signed. 
 
 
Flowchart 
 
To be performed at baseline: 
 
Informed consent(s) signature 
 
Measure of serum antibodies against HPV 6/11/16/18/31/33/45/52/58 (1 10 
ml tube) by 9cLIA by Merck USA. 
 
Measure of lymphocytes T CD4+ level and HIV viremia if there is no previous 
sample up to 6 months before baseline. 
 
Cervical smear on a liquid based samples (Cytoprep) taken by the 
gynecologist for cytology and HPV detection (to be performed by the national 
reference centre for HPV, AML, Antwerpen) if there is no previous sample up 
to 6-12 months before baseline. These samples will not be taken if the 
participant has never experienced vaginal sexual intercourse. 
 
ONLY FOR THE CELLULAR IMMUNE RESPONSE SUBSTUDY: an additional 
specific IC should be signed and a sample of 50-100 ml should be taken. 
 
Randomisation (after December 2018 amendment): patients will be allocated 
to one of the two arms by random randomization through a software 
program. The result of the allocation will be known to the patient, to his 
healthcare providers and to the study team. 
 ARM A: vaccination at time 0 and  6 and a later booster if needed 
 ARM B: vaccination at time 0, 2 and  6 months 
 Vaccine administration after randomisation 
Gardasil9 (Merck®) first dose will be administrated intramuscularly in the deltoid 
while the patient is lying down. The patient will remain lying 15 minutes after the 
injection. 
 
First safety assessment after vaccination 
The patient will be contacted by phone by the research team scheduled at least 48 
hours and maximum 7 days after vaccine dose to evaluate the safety and tolerance 
of the vaccine with a questionnaire on local reaction (size, redness, pain and 
swelling), systemic reaction (fever, malaise and fatigue) or any other side effect. In 
case of any usual complain > grade mild, or the presence of an unusual complain, 
the patient will be assessed by a visit and physical examination performed by the 
research team.  
 

19 
 
Month 2 (only for patients in ARM B) 
Gardasil9 second dose will be administrated intramuscularly in the deltoid while the 
patient is lying down. The patient will remain lying 15 minutes after the injection. 
 
Second safety assessment after vaccination 
The patient will be contacted by phone by the research team scheduled at least 48 
hours and maximum 7 days after vaccine dose to evaluate the safety and tolerance 
of the vaccine with a questionnaire on local reaction (size, redness, pain and 
swelling), systemic reaction (fever, malaise and fatigue) or any other side effect. In 
case of any usual complain > grade mild, or the presence of an unusual complain, 
the patient will be assessed by a visit and physical examination performed by the 
research team.  
 
Month 6 
Gardasil9 second (ARM A) or third (ARM B) dose will be administered 
intramuscularly in the deltoid while the patient is lying down. The patient will remain 
lying 15 minutes after the injection. 
 
Second (ARM A) or third (ARM B) safety assessment after vaccination 
The patient will be contacted by phone by the research team scheduled at least 48 
hours and maximum 7 days after vaccine dose to evaluate the safety and tolerance 
of the vaccine with a questionnaire on local reaction (size, redness, pain and 
swelling), systemic reaction (fever, malaise and fatigue) or any other side effect. In 
case of any usual complain > mild, or the presence of an unusual complain, the 
patient will be assessed by a visit and physical examination performed by the 
research team.  
 
Month 7 
Measure of lymphocytes T CD4+ level and HIV viremia. 
Measure of serum antibodies against HPV 6/11/16/18/31/33/45/52/58 (1 10 ml 
tube) 
 
ONLY FOR THE CELLULAR IMMUNE RESPONSE SUBSTUDY: a sample of 50-100 ml 
will be taken. 
 
 
 
Month 18-24 
 
Measure of serum antibodies against HPV 6/11/16/18/31/33/45/52/58 (1 10 
ml tube) by IgG LIA by Merck USA. 
 
 
Cervical smear on a liquid based samples (Cytoprep) taken by the 
gynecologist for cytology and HPV detection. These samples will not be taken 
if the participant has never experienced vaginal sexual intercourse. 
 
 
 
 

20 
 
Procedures for Collection and Handling of Study Specimens: 
 
1/Measure of serum antibodies against HPV 
6/11/16/18/31/33/45/52/58 (one 10 ml tube) 
 
 
For each visit that requires a serum specimen for anti-HPV measurements, a 10 mL 
(nonheparinized, non-serum separator, red-top tube) blood specimen will be 
collected and will be separated to avoid hemolysis. A minimum of 3 mL of serum will 
be aliquoted to a vial. An additional 1.5 mL of serum (Retention Serum) will be 
aliquoted to a vial. 
After the serum has been processed, the vials will be transfered to the freezer (-
20°C or lower) without delay. All serum samples will be kept in the freezer until 
they are shipped on dry ice; the transport tube will be a 2ml cryovials. 
  
Centrifuging will be done per protocol with sera frozen. 
 
“Serum” vials will be stored at the site at -20°C (or lower) until shipped on dry ice 
to the lab. The freezer used to store the vials must be a non-frost-free freezer. All 
available serum will be used for conducting assays specified in the clinical protocol. 
Serum may also be used during the clinical trial, for further HPV immunologic 
testing in addition to tests specified in the protocol. 
  
Retention Serum vials will remain stored at the site at -20°C (or lower). The freezer 
used to store the vials must be a non-frost-free freezer. The site will ship "Retention 
Serum" separately from the "Serum" sample.  
 
The rest of the sample will be kept on site frozen as a backup sample. 
  
 
Booster dose in ARM A 
A third booster dose of Gardasil9 will be given in women from ARM A if they fail to 
develop antibodies against any of the HPV genotypes contained in the vaccine. As 
the analysis of the antibodies will be performed in MERCK laboratory in the USA in 
batches, the booster dose will be given as soon as the results of the antibodies 
measurement will be known which is predicted to be as soon as possible just after 
Month 7 of the last enrolled patient. 
 
 

21 
 
2/ Immune cellular response: PBMC procedure 
 
Abbreviations and codes 
 
• 
LAF – Laminar air flow 
• 
RT – Room temperature 
• 
PBMC – Peripheral Blood Mononuclear Cell 
• 
EDTA – Ethylenediaminetetraacetic acid 
• 
PBS – Phosphate buffered saline 
• 
RPMI – Roswell Park Memorial Institute 
• 
FCS – Fetal calf serum 
• 
DMSO – Dimethyl sulfoxide 
 
1 Material 
Equipment 
 
Laminar air flow (LAF) 
 
Centrifuge for large tubes and small eppendorf tubes 
 
Pipette boy 
 
Pipettes: P20, P200, P1000 
 
Light microscope 
 
Refrigerator 
Material 
 
Gloves 
 
Laboratory wipes 
 
70% cleaning ethanol 
 
Pipettes: 5mL, 10mL, 25mL 
 
15mL Falcon tubes 
 
50mL Falcon tubes 
 
Cryovials 
 
Appropriate label for cryovial (see SOP01 labelling) 
 
1,5mL eppendorf tubes 
 
2x 2ml EDTA tubes (only for visit one of each patient for genetic testing) 
 
Lymphoprep 
 
Leucosep tubes  
 
CryoStor®complete cryopreservation medium 
 
PBS or RPMI 1640 (without EDTA) 
 
Trypan blue 
 
Counting chamber 
 
Cryostor (Freezing medium) 
 
Freezing container (precooled) 
 

22 
 
2 Method 
 
 
Switch on LAF and clean surface using 70% ethanol. 
 
The first visit: of each patient after inclusion (M0) demands a whole blood sample for 
genetic testing. Therefore fill two EDTA tubes of 2ml with 1ml blood, label and store at 
-80°C prior to continue with PBMC isolation. 
 
Add 15mL Lymphoprep solution on the polyethylene membrane of a 50mL leucosep 
tube. 
 
Centrifuge 2 min at 200 x g at RT. 
 
Add EDTA blood on the membrane of a Leucosep tubes (normally 3x9ml EDTA blood 
in one tube). 
 
Centrifuge for 20 min at 880 x g at RT (switch off breaks in the centrifuge for proper 
separation!). 
 
Aspirate the plasma (top layer) and transfer to a 15mL tube. The plasma should be 
divided in 5 fractions of 2 ml and the rest in fractions of 14 ml. 
o 
Prepare 5 aliquots of 2 mL plasma in 2mL tubes and aliquots of 14 ml in 15 ml 
tubes and store at -80°C.  
o 
Label with patient study number, study visit code and date of sampling (see 
SOP01 labelling). 
 
Aspirate the white ring of PBMCs and transfer to a 50mL tube.  
 
Top up with RPMI or PBS (without EDTA!) until the 50mL mark to wash the sample. 
 
Centrifuge for 10 min at 880 x g at RT. 
 
Discard the supernatant (SN) without disturbing the pellet. 
 
Resuspend the pellet in 10 ml PBS or RPMI (without EDTA). 
 
Count PBMCs with a counting chamber. 
 
Continue with section below (preparation of cells in CryoStor®)  
Preparation of cells in CryoStor® 
o 
Take cell material and centrifuge for 10 min at 880 x g. 
o 
Resuspend the pellet at 20 x 106 cells per ml in CryoStor® complete freezing 
medium 
o 
Aliquot 4 x 500ul (= 10 x 106 cells) into cryotubes and top with 500 ul of 
CryoStor® (equals 10x106 cell aliquots). Distribute the rest of cells by adding 1 
ml (= 20 x 106 cells) of the cell suspension per cryovial. 
 
 

23 
 
o 
Label cryovials with from LIH provided labels (for details see labelling SOP 01) 
1. Patient study number 
2. PhenoCure study visit 
3. Amount of cells 10 x 106 PBMCs or 20 x 106 PBMCs 
4. Date of sampling (dd/mm/yyyy) 
o 
Make sure that the patient specific study number on the label correlates with 
the eCRF by making a note to the clinician! 
o 
Put the vials in a pre-cooled (4°C) Mr. Frosty and immediately put the Mr. 
Frosty at -80°C. 
o 
Leave the samples at -80°C overnight and transfer them to liquid nitrogen the 
next morning. 
 
Samples in Cryostor® should not be kept at -80°C for longer than 24h! 
 
 
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