Preventive Medicine Reports 35 (2023) 102368

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Preventive Medicine Reports

journal homepage: www.elsevier.com/locate/pmedr

An update on one-dose HPV vaccine studies, immunobridging and humoral

immune responses – A meeting report
Dur-e-Nayab Waheed a, F. Ricardo Burdier a, Carina Eklund b, Iacopo Baussano c,
Filipe Colaço Mariz d, Laura Téblick a, Nelly Mugo e, Deborah Watson-Jones f, Margaret Stanley g,
Marc Baay h, Alex Vorsters a, *
a
Centre for Evaluation of Vaccination, Vaccine and Infectious Disease Institute, University of Antwerp, Belgium
b
Karolinska Institutet, Department of Laboratory Medicine, Huddinge, Sweden
c
International Agency for Research on Cancer, Early Detection, Prevention and Infections Branch Lyon, France
d
German Cancer Research Center, DKFZ, Tumorvirus-Specific Vaccination Strategies, Heidelberg, Germany
e
Kenya Medical Research Institute, Nairobi, Kenya
f
Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
g
Department of Pathology, University of Cambridge, Cambridge, United Kingdom
h
P95 Epidemiology & Pharmacovigilance, Leuven, Belgium

A R T I C L E I N F O A B S T R A C T

Keywords: The 12th HPV Prevention and Control meeting was held on June 2–3, 2022, in Antwerp, Belgium. This technical
Human papilloma virus meeting focused on several topics. This report summarises the discussions and lessons learned on two topics: an
Vaccination update on one-dose HPV vaccination studies and humoral immune responses upon HPV vaccination. Long-term
Schedule
follow-up studies from Costa Rica (eleven years) and India (ten years) report stable levels of antibodies after a
One dose
Immunobridging
single HPV vaccination. High vaccine effectiveness against incident persistent HPV 16/18 infection was seen in
Humoral immune responses India (95.4%, 85.0–99.9) ten years postvaccination and in Kenya (97.5%, 81.7–99.7) eighteen months post­
Clinical trials vaccination, an important observation in a setting with a higher HPV prevalence. The potential impact of HPV
Meeting report vaccination using a one-dose schedule in India was modelled and showed that implementation of one-dose
schedule can contribute towards achieving WHO Cervical Cancer elimination goals. These data support the
WHO SAGE recommendations for adopting a one-dose schedule for females aged 9–20 years. Immunobridging
studies were discussed during the meeting. General agreement was reached that when thoughtfully applied, they
can support and accelerate the expanded use of HPV vaccine with new vaccine schedules, age cohorts, or vaccine
formulations. Internationally standardised measurements of HPV immune responses important for the progress
of HPV vaccinology field. Humoral immune responses upon HPV vaccination plateau at 24 months regardless of
number of doses, therefore, data should be analysed after at least 24 months of follow-up to bridge studies
accurately.

Abbreviations: 2vHPV, Bivalent HPV vaccine; 4vHPV, Quadrivalent HPV vaccine; 9vHPV, Nonavalent HPV vaccine; CVT, Costa Rica vaccine trial; DoRIS, A DOse
Reduction Immunobridging and Safety study; FCM, Finish Maternity Cohort; FVU, First-Void Urine; GMC, Geometric Mean Concentration; HIV, Human Immuno­
deficiency Virus; HPV, Human Papillomavirus; IARC, International Agency for Research on Cancer; KEN SHE, KENya Single dose HPV vaccine Efficacy study; MCV,
Meningococcal Vaccine; Nabs, Neutralizing antibodies; PBNA, Pseudovirion-Based Neutralization Assay; SWOT, Strengths, Weaknesses, Opportunities, and Threats;
VE, Vaccine Efficacy; VLP, Virus-like particle; WHO, World Health Organization.
* Corresponding author at: Centre for the Evaluation of Vaccination, Vaccine and Infectious Disease Institute, University of Antwerp, Drie Eikenstraat 663, 2650
Edegem, Belgium.
E-mail addresses: [email protected] (D.-e.-N. Waheed), [email protected] (F.R. Burdier), [email protected] (C. Eklund),
[email protected] (I. Baussano), [email protected] (F.C. Mariz), [email protected] (L. Téblick), [email protected] (N. Mugo), deborah.
[email protected] (D. Watson-Jones), [email protected] (M. Stanley), [email protected] (A. Vorsters).

https://doi.org/10.1016/j.pmedr.2023.102368
Received 21 April 2023; Received in revised form 9 August 2023; Accepted 13 August 2023
Available online 14 August 2023
2211-3355/© 2023 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND IGO license (http://creativecommons.org/licenses/by-nc-
nd/3.0/igo/).
D.-e.-N. Waheed et al. Preventive Medicine Reports 35 (2023) 102368

1. Introduction immunity. All vaccinated cohorts had a similar incidence of HPV16/18

infections [one-dose cohort 3.1 (2.6–3.8) vs two-dose regimes 2.6
The HPV Prevention and Control Board is an independent, interna­ (2.0–3.3) vs 3-dose cohort 3.0 (2.3–3.8)] while the control arm had an
tional, and multidisciplinary group of experts, created in 2015 to pro­ increased incidence [unvaccinated 9.7 (8.2–11.3)]. Adjusted VE for
vide evidence-based guidance and reflection on strategic, technical, and incident persistent HPV 16/18 infections was 93.3% (77.5–99.7) for the
policy issues regarding the implementation and sustainability of HPV three-dose cohort, 93.1% (77.3–99.8) for the two-dose cohort, and
prevention and control programmes. The board aims to disseminate and 95.4% (85.0–99.9) for the one-dose cohort.
amplify relevant information on HPV prevention and control to a broad Two important randomised controlled trials aiming to evaluate one
array of stakeholders by organising two meetings every year; a technical dose HPV VE are currently ongoing in Tanzania and Kenya.
meeting covering topics such as vaccine characteristics, vaccine safety, The KEN SHE Study investigates one-dose HPV vaccination between
screening technologies and landscape, treatment strategies, the role of Gardasil-9® (9vHPV) Cervarix® (2vHPV) VE for incident persistent HPV
healthcare providers in vaccination programmes, and dealing with anti- infection among sexually active adolescent girls and young women in
vaccine messages (Vorsters et al., 2017; Vorsters et al., 2019; Waheed Kenya. At month 18 the incidence persistence of non–vaccine-type HPV
et al., 2021); and a country meeting, covering a strengths, weaknesses, infections was similar between study arms, ranging from 22.2 to 24.5
opportunities, and threats (SWOT) analysis of a country or region HPV per 100 woman-years. However, the incidence persistence of HPV16/18
prevention and control programs (Vorsters et al., 2020). infections was significantly lower in 2vHPV and 9vHPV than in the
The objectives of the meeting were focused on: control arm (0.17 in both study arms vs 6.83 per 100 woman-years),
with a VE of 2vHPV of 97.5% (81.6–99.7) and 9vHPV of 97.5%
1) One-dose HPV vaccination studies: (81.7–99.7) See Table 1 (Barnabas et al., 2022). Finally, the incidence of
- Update on efficacy and effectiveness data on HPV vaccination one- HPV16/18/31/33/45/52/58 infections (the vaccine types in the non­
dose schedule. avalent vaccine) was significantly lower in the 9vHPV study arm than in
- Evaluate immunobridging results from current one-dose HPV the control arm (1.03 vs 9.42 per 100 woman-years, VE = 88.9%
vaccination trials to historical one-dose efficacy data. (68.5–96.1) See Table 1.
- Discuss the global recommendation landscape of HPV vaccination The Dose Reduction Immunobridging & Safety Study (DoRIS) offered
one-dose schedule. one, two or three doses of the 2vHPV (Cervarix®) or 9vHPV (Gardasil-
2) Humoral immune responses upon HPV immunization: 9®) vaccine in order to demonstrate non-inferiority of HPV16/18
- Availability and use of standardized measurements for reporting seroconversion after one dose compared with two or three doses of the
humoral immune responses. same vaccine. At month 36, one dose was non-inferior to two doses and
- Characterisation of humoral immune responses for evaluating HPV three doses for HPV16 for both vaccines, but for HPV18 non-inferiority
vaccines immunogenicity. was only met for two doses versus three doses for both 2vHPV and
- First-void urine as a sampling mechanism to evaluate humoral 9vHPV. HPV16/18 antibody levels after one dose reached plateau from
immune responses. month 12 to month 36 for both vaccines. The HPV 16/18 avidity index
was very similar between one dose, two doses, and three doses, for both
This report presents an overview of available data and discussions vaccines and both HPV types, with avidity index ratios close to 1.
taking place during the June 2022 meeting. It is worth noting that not all Given the challenge of recruiting and sampling younger age cohorts
available studies on the topics are included due to data availability. to evaluate the efficacy of HPV vaccines, immune responses were
Furthermore, the allocated time of 0.5 days for this topic within the bridged to populations where efficacy has been shown. Similar to the
meeting restricted the time available for in-depth discussion of certain original licensure of HPV vaccines, non-inferiority of immune responses
subtopics. Despite these limitations, the discussions held among authors were used to infer efficacy in younger girls through a comparison of anti-
and various experts from academia, regulatory authorities, and other HPV ELISA titres (IARC, 2014). Historic efficacy data used for immu­
stakeholders are unique and provide important discussion points nobridging include antibody levels from CVT (11yearsfollowup), India
essential for future research. IARC (10yearsfollowup) and KEN SHE (18 months).
For all these trials, after one dose HPV vaccination schedule, anti­
2. Updates on one-dose HPV vaccination studies body levels in DoRIS were shown to be non-inferior for HPV16 and 18,
for both 2vHPV and 9vHPV in comparison to the similar vaccine in the
Over the past few years, there has been growing evidence that a older aged efficacy populations. See Table 1.
single dose of HPV vaccine can provide protection against cervical
cancer. Long-term follow-up data is available from the Costa Rica HPV 2.1. Prospects: Studies investigating the efficacy and impact of one-dose
Vaccine Trial (CVT, launched in 2004) conducted prior to licensure of HPV vaccination in preventing cervical cancer
2vHPV (Cervarix®) in 18–25-year-old women using three doses; In the
CVT trial the vaccine efficacy (VE) of the one dose group for prevalent The ESCUDDO trial compares the efficacy of one versus two doses of
HPV 16/18 infection was 82.1% (40.2–97.0) at 11.3 years after vacci­ 2vHPV (Cervarix®) and 9vHPV (Gardasil-9®) vaccines in Costa Rican
nation. HPV16 serum antibodies are stable after a follow-up of 11 years girls aged 12–16, with results expected in 2025.The PRIMAVERA trial,
in participants that received one, two and three doses. Immunologic an immunobridging trial comparing antibody levels in girls receiving
follow-up is set to continue for up to 20 years (Kreimer et al., 2020) See one dose of 2vHPV from ESCUDDO to those receiving three doses of
Table 1. 4vHPV (Gardasil-4®) in historical cohorts, with results expected by
Furthermore, the India IARC trial, a multicentric cohort study to 2023/2024.
compare the efficacy of a two-dose versus three-dose 4vHPV (Gardasil- The PRISMA study evaluates the efficacy of one dose of 2v- (Cer­
4®) schedule in 10–18-year-old females in India, provides 10-year varix®) and 9vHPV (Gardasil-9®) vaccines against persistent HPV16/18
follow-up data on one dose efficacy (Basu et al., 2021). After the sus­ cervical infections in HPV16/18-DNA baseline negative women aged
pension of recruitment and vaccination, the study became a longitudi­ 18–30, with data expected by 2027. This will provide an opportunity to
nal, prospective cohort study by default. Participants were allocated to protect additional women from HPV-related disease, as a one-dose
four cohorts based on the number and timing of vaccine doses received. schedule in adult women may allow for a massive, one-time catch-up.
See Table 1 for further details. At 10 years post-vaccination, 96% and The HOPE study was set up to monitor the impact of a two-dose and
97% of one-dose recipients had detectable HPV16 and HPV18 anti­ one-dose HPV vaccination schedule on community-level HPV preva­
bodies, respectively, with titres 15 and 10 times higher than natural lence using repeat cross-sectional surveys, collected from independent

2
 Table 1

D.-e.-N. Waheed et al.

Summary of studies studying efficacy and immunogenicity of cohorts that received one-dose regime of any HPV vaccine product.
Study acronym. Location. Objectives Vaccine Population Age Sample Timing of Results
(Clinical Trial #) Product size measure
Status Cohorts

KEN SHE KENya Single-dose HPV-vaccine Individual randomised, double blind, Women 15–20 years old. Month 18 •Incident persistent HPV 16/18 infections was VE (95% CI)
Efficacy control, three group study. significantly lower in vaccine group.
Kenya. 1. Test efficacy of immediate single-dose 9vHPV (N = 750) - mITT at m18 (9vHPV) 97.5(81.7–99.7)
(NCT03675256). Active, not recruiting. 9vHPV vs 2vHPV vs MCV control) vs
vaccination to prevent incident persistent 2vHPV (N = 750) - mITT at m18 (2vHPV) 97.5(81.6–99.7)
HPV 16/18 infection Vs
2. Test efficacy of immediate single-dose MCV (N = 750) • Incidence of HPV 16/18/31/33/45/52/58
9vHPV to prevent incident persistent HPV infections
16/18 /31/33/45/52/58 - mITT at m18 88.9 (68.5–96.1)
• These data provide strong evidence for single-dose
HPV vaccine efficacy, showing that adolescent girls
and young women were effectively protected from
HPV infection over the first 18 months after
vaccination.

DoRIS A Dose Reduction Immunobridging Open label randomised study of two Girls 9–14 years old. Month 24 • >99% HPV 16 seropositive and > 98% HPV 18
and Safety Study. different HPV vaccines. 2vHPV seropositive.
Tanzania. (NCT02834637). Active, not 1. Demonstrate non-inferiority of HPV 16/ 1D N = 155 •Non-inferiority for seroconversion was met (1D is
recruiting. 18 seroconversion after 1-dose vs 2-dose 2D N = 155 not inferior than 2D/3D) for HPV 16 for both
and 3-dose of same vaccine at M24. 3D N = 155 vaccines.
2. Immunobridging: Demonstrate non- vs • For HPV18, non-inferiority of 1D was not met.
inferiority of HPV 16/18 ab GMT at M24 9vHPV • HPV 16/18 Ab concentrations on 2D and 3D cohorts
1D DoRIS vs historical efficacy cohort on 1D N = 155 declined after peak in M7, while 1D cohort
1D. 2D N = 155 concentration remain constant from M7.
• Avidity index similar between dose groups, for
3

HPV16 and HPV18, for both vaccines products.

3D N = 155 • 1D in DoRIS is non-inferior to 1D in historical GMC ratio
cohorts at M24,for HPV-16 & HPV-18, for both (95% CI).
vaccines.
○ 2vHPVDoRIS vs 2vHPV CVT (HPV 16) 1.30 (1.00–1.68)
○ 9vHPV DoRIS vs 4vHPV India (HPV 16) 1.29 (0.91–1.82)
○ 2vHPV DoRIS vs 2vHPV CVT(HPV 18) 1.23 (0.95–1.60)
○ 9vHPV DoRIS vs 4vHPV India (HPV 18) 1.75 (1.22–2.50)

CVT Costa Rica Vaccine Trial. Extended follow-up of young women from 2vHPV Woman who 11 years • Vaccine effectiveness for persistent HPV16/18 VE (95% CI)
Costa Rica. (NCT00867464). CVT Phase III. Evaluate impact of HPV 16/ participated in the Phase infection with 1D is above 80%. 82.1 (40.2–97)
Active, not recruiting. 18 immunisation. Evaluation of immune III CVT. • HPV16 or 18 antibody levels did not qualitatively
responses and HPV-related disease. (18-25y/o) Some women decline between years four and 11 regardless of the
missed visits, only number of doses given.
received 1-dose. (N=
112).

Preventive Medicine Reports 35 (2023) 102368

Trial of two vs three Doses of Human Multi-centre cluster randomised trial of 4vHPV Woman 10–18 y/o 10 years. • HPV 16/18: 96%/97% of one-dose recipients had VE (95% CI)
Papillomavirus (HPV) Vaccine in India. two vs three doses of 4vHPV in India. 3D N=4,348 detectable Ab at 10 years; Ab titre was 15X/10higher
India. Suspension of the vaccination led to per 2D (0-6m) N=4,980 than natural immunity.
(NCT00923702) protocol and partial vaccination of 2D (0-2m) N=3,452 • Adjusted VE against HPV16/18 persistent infection.
Active, not recruiting. unmarried 10–18 y/o girls. 1D N=4,949. ○ 3D 93.3 (77.5–99.7)
○ 2D 93.1 (77.3–99.8)
○ 1D 95.6 (85.0–99.9)
• Incident infection from HPV 31, 33, 45 Incidence (95%
CI)
○ 3D 4.8 (4.0–5.6)
○ 2D 4.1 (3.3–5.0)
○ 1D 4.1 (3.4–5.1)
○ Non vaccinated 10.5 (9.0–12.12)

(continued on next page)

 D.-e.-N. Waheed et al.
Table 1 (continued )
Study acronym. Location. Objectives Vaccine Population Age Sample Timing of Results
(Clinical Trial #) Product size measure
Status Cohorts

HOPE HPV One and two-dose Population Aims to monitor the effectiveness of a 2D 2vHPV Girls (> 9 y/o) Impact survey 1 One-dose analysis in progress.
Effectiveness. and 1D HPV vaccination schedules on (2D) (N=6673) 28% carried out. • Manuscript in preparation
South Africa. community-level HPV prevalence among vs unvaccinated 72%
South African adolescent girls. 2vHPV vaccinated.
(1D)

PRIMAVERA Puente de Respuesta Demonstrate non-inferiority of the ab 2vHPV Girls (9–14 y/o) Serology at month 12, Expected results by 2023–2024.
Inmunológica Para Mejorar el Acceso a response in girls who receive 1D 2vHPV vs (1D) (N= 620) 24 and 36
Vacunas y ERrAdicar el Cancer. young women who receive 3D of 4vHPV. vs Woman
Costa Rica. (NCT03728881) 4vHPV (18-25y/o). (N=620).
Active, not recruiting. (3D)

ESCUDDO Estudio de Comparacion de Una Evaluation of 1D or 2D of vaccine against 2vHPV Girls (12–16 y/o) Serology, cytology Results expected by 2024/2025
y Dos Dosis de Vacunas Contra el Virus de HPV with randomised parallel assignment (1D) (N= 20,300) and urine at months
Papiloma Humano (VPH). Costa Rica. of vaccine product 2vHPV vs 9vHPV and Vs 12, 18, 24, 30, 36, 42,
(NCT03180034) dose regime 1D vs 2D. 2vHPV 48, 54, 60.
Enrolling by invitation. (2D)
vs
4

9vHPV
(1D)
vs
9vHPV
(2D)

PRISMA PRevencion del cancer de cervix Randomised, blinded, controlled trial. 9vHPV Woman (18-30y/o) Serology, cytology • Study launched
con una sola dosIS de vacuna contra VPH Evaluate one dose of the HPV vaccines (1D) (N=5,000+) and urine at months • Goal is to have data ready for 2027, when HPV
en Mujeres Adultas jovenes. compared to no vaccination in the vs 12, 18, 24, 30, 36, 42, vaccine supply exceeds demand
Costa Rica (NCT05237947) protection against incident HPV16/18 4vHPV 48, 54, 60. • The study is an opportunity to save additional
Enrolling by invitation cervical HPV infections that persist six (1D) women- 1 dose in women may allow for a massive,
months or more in women 18 to 30 y/o vs one-time catch-up
who are HPV16/18 DNA–negative prior to 2vHPV
and at the time of vaccination (1D)

mITT: Modified intention-to-treat, y/o: years old, ab: antibodies, VE: Vaccine efficacy, GMC: Geometric Means Concentration, MCV: Meningococcus vaccine, CI: Confidence Interval, M: Months, 1D: 1-dose, 2D: 2-dose. 3D:
3-dose, CVT: Costa Rica Vaccine Trial. 9vHPV: nonavalent HPV vaccine (GARDASIL 9, Merck Sharp & Dohme Corp), 4vHPV: quadrivalent HPV vaccine (Gardasil 4; Merck & Co., Inc), 2vHPV: bivalent HPV vaccine

Preventive Medicine Reports 35 (2023) 102368

(Cervarix; GlaxoSmithKline), MCV: meningococcal vaccine (MENVEO; GlaxoSmithKline).
D.-e.-N. Waheed et al. Preventive Medicine Reports 35 (2023) 102368

cohorts of South African adolescent girls, from before (“pre-vaccine recommended. SAGE recommended that countries, where feasible and
cohort”) and after (“vaccine eligible cohort”) implementation of the affordable, prioritise a catch-up of older cohorts and missed girls
programme. Additionally, the investigators wanted to measure the through multi-age cohort vaccination. Introducing the vaccination of
population impact of a one-dose vaccine schedule, delivered as a catch- boys and older females should be carefully managed until the global
up, to Grade 10 pupils in one district, in protecting against infection with supply situation is fully resolved. Where gender-neutral vaccination is
HPV16 and/or 18 (Machalek et al., 2022). introduced, males can receive the same schedule as females (World
Of 6,673 potential recipients, 4,807 (72%) received a single HPV Health Organization, 2022).
vaccine dose. The median age of the vaccine recipients was 16 (inter­ Data gaps that still exist are: first, the immunogenicity, protective
quartile range 15–17) years. The primary reason for non-vaccination efficacy, and duration of protection, with reduced-dose schedules in
was lack of signed parental consent or absenteeism (98%). Analysis of immunocompromised individuals, especially the level of protection
the data is currently in progress. See Table 1 for further details of these provided when HIV seroconversion happens after one dose of HPV
trials. vaccine; second, long-term immunogenicity, efficacy, and duration of
protection of one-dose HPV vaccine schedule in girls and boys 9–14
2.2. Evidence-based impact projections of single-dose HPV vaccination in years old; third, the use of one-dose schedules in older adults and chil­
India dren below 9 years of age; and finally, implementation research to
identify strategies to improve HPV vaccine coverage, including among
EpiMetHeos model was used to predict the impact of HPV vaccina­ populations at high risk of early HPV infection and immunocompro­
tion under the one-dose schedule in India, looking at its effectiveness on mised individuals (World Health Organization, 2022).
HPV infection and cervical cancer, the potential of elimination accord­
ing to different indicators, the relative efficacy of one-dose compared to 2.4. Panel discussion on one-dose HPV vaccine trials and introduction of
the two-dose schedule, the impact of catch-up, and the variability of a one dose schedule
impact across India (Man et al., 2022).
Four scenarios were used, based on India IARC trial 10 year efficacy During the panel discussion, experts involved in the previously
data where vaccine efficacy of incidence persistent infection for HPV16/ presented clinical trials had the opportunity to discuss among them,
18 is 95% and HPV31/33/45 is 9%. Scenario A assumed lifelong vaccine raising relevant points and concerns from the evidence showed.
protection for both, single-dose and two-dose HPV vaccination. Scenario
B assumed similar initial HPV16/18 VE (95%/95%) but waning of 2.4.1. Background HPV prevalence and selection bias
protection for single-dose vaccination. Scenario C, similar to assumption Several attendees raised the concern of one-dose HPV vaccine per­
B, but lower initial HPV 16/18 VE (90%/85%) and faster waning of formance being subject to the difference in background HPV prevalence
protection for single-dose vaccination. Lastly, scenario D with lower in the settings where these trials were carried out. The data from the
initial HPV 16/18 VE (85%/55%) and faster waning of protection for KEN SHE study seem to argue against this suggestion where single-dose
single-dose vaccination. These assumptions were derived from the lower HPV vaccination provides high efficacy against incident persistent HPV
bound of efficacy estimated by the IARC India HPV vaccine trial and by 16/18 infection even in the setting of a high incidence of HPV infection.
projecting the time until HPV16 and HPV18 antibody levels observed in Although the efficacy follow-up in KEN SHE is relatively short (18
the trial decreased below predefined thresholds. months) and the antibody levels in participants receiving two or three-
The base-case scenario reached the WHO elimination threshold in dose schedules is considerably higher across studies, there are sugges­
the long term, with a 71% reduction in cervical cancer risk in the first tions that immune responses will be stable over time as presented from
five vaccinated cohorts. With the three alternative scenarios, elimina­ the African setting study (DoRIS) in Tanzania. Moreover, in all presented
tion was still attained in most scenarios. Furthermore, under any sce­ trials measuring one dose schedule, immunogenicity reports minimal
nario, the two-dose schedule needed more doses than the one-dose HPV 16/18 antibody decay after plateau. Similar observations were
schedule to prevent one case of cancer, 26% more under the less presented in Costa Rica and India, where 10 years of follow-up has been
favourable set of assumptions. Hence, in most scenarios the one-dose done. DoRIS data presented during the meeting showed stable immune
schedule is cost-saving (when undiscounted) and cost-effective (when response at 3 years after a single dose of HPV vaccine. This may suggest
discounted), whereas introducing a second dose is not cost-effective that regardless of the number of doses administered, there is a stable
(Man et al., 2022). These projections indicate that single-dose vaccina­ long-lived plasma cells niche produced which continue to generate an­
tion can substantially decrease cervical cancer burden across India and tibodies. Results from the HOPE study are expected to provide insight on
that some Indian states with the highest burden would benefit from the impact and effectiveness of one-dose HPV vaccination schedule at a
additional control measures. wider level.

2.3. Update on SAGE advice on HPV schedule optimisation and the 2.4.2. Genotype replacement
permissive single-dose recommendation in younger women Levels of protection elicited by one-dose HPV vaccination were
raised as a point of concern, specifically with uncertainties of reduced
High interest in HPV vaccination by countries across all income dose schedules to allow type-replacement of oncogenic genotypes.
groups has resulted in increased demand in the past several years. However, for type replacement to take place there needs to be compe­
However, a combination of factors, primarily linked to continued supply tition, which is not seen at a lesion level. Although multiple infections
constraints, has slowed the pace of introductions, particularly in low- can be found, lesions are known to be driven by only one genotype.
resource settings (WHO Health Organization, 2022). It was in this Furthermore, characterisation of humoral responses following HPV
setting that the WHO Strategic Advisory Group of Experts on Immuni­ vaccination have not shown results suggesting type replacement, in the
zation (SAGE) took up a review of the new evidence around HPV contrary, the responses have suggested to be more cross-protective than
reduced dose schedule in 2022. expected. According to transmission modelling, however, it is still too
SAGE advised that the target population for vaccination should early to preclude type replacement and monitoring of non-vaccine types
remain 9–14-year-old girls. For this target population, one dose or two remains pivotal (Man et al., 2021).
doses can be used. Similarly, for 15–20-year-olds, one dose or two doses Clinical trials are a good setting to investigate possible vaccine fail­
can be used, whereas, from the age of 21, a two-dose schedule can be ures by looking at breakthrough cases. In CVT trials, there are currently
used. Finally, regardless of age, at least two doses should be used in eight possible vaccine failures among the ~ 3000 women in the vacci­
immunocompromised patients, while ideally, three doses are nated arm, who had on average 11 years of follow-up. Investigations to

5
D.-e.-N. Waheed et al. Preventive Medicine Reports 35 (2023) 102368

confirm these cases as vaccine failure include persistence of HPV International monospecific standard sera have been established for
infection that has not been detected in previous follow up, antibody HPV16 and HPV18 (Faust et al., 2016; Ferguson et al., 2011), while
levels and avidity and viral variance studies. work on sera for HPV6, 11, 31, 33, 45, 52 and 58 is ongoing. Secondly,
reproducible methods for analysing readouts should be used. The par­
2.4.3. Implementation of HPV one-dose schedule in settings with high HIV allel line method is the method of choice, as it increases reproducibility
prevalence (Grabowska et al., 2002).
Questions regarding the impact of HPV vaccine–induced protection In a head-to-head comparison (vaccine induced antibodies against
among people who will acquire HIV after being vaccinated with one pseudovirions from 17 different HPV types [HPV6/11/16/18/31/33/
dose HPV vaccination were raised. This is especially concerning in Sub- 35/39/45/51/52/ 56/58/59/66/68/73]), using the standardised sera
Saharan Africa, where six out of seven new HIV infection in adolescents and the parallel line method, the 2vHPV Cervarix® vaccine induced
aged 15–19 years occurs in girls (Schiller and Müller, 2015; UNAIDS higher antibody titres to HPV16 and HPV18 than the 9vHPV. Also, the
data, 2022). analysis suggested that the 2vHPV(Cervarix®) and 9vHPV vaccines may
In persons living with HIV, HPV vaccination induce high rates of afford some cross-protective efficacy against HPV35. International Units
antibody seroconversion (Toft et al., 2014; Faust et al., 2016) and are useful to quantitate the level of protection afforded, and new vaccine
vaccine-induced antibody responses are sustained for at least four years formulations that include HPV35 may need to be considered (Arroyo
(Levin et al., 2017), but cross-reactive antibody responses were dimin­ Mühr et al., 2022).
ished as compared to that reported in HIV-negative populations. Despite
the reasonable evidence supporting the immunogenicity of HPV vac­ 3.2. Neutralising and cross-neutralising antibody levels to HPV following
cines in HIV-positive individuals, the corresponding efficacy data is vaccination
inconsistent (Lacey, 2019). Further research is needed to understand the
functional and anatomical immunologic remodelling that occurs in HIV HPV vaccines induce a type-specific neutralising antibodies (NAb)
infection in regard to HPV-vaccine-induced protection. A major question response directed to the L1 loop regions exposed on the HPV capsid
for further research is looking at the impact of an HIV infection after surface. Anti-L1 antibodies can reach the cervix via transudation from
HPV vaccination. This can only be investigated in areas with high HIV the systemic circulation and are postulated to be the primary mechanism
incidence. The question remains whether this will reduce the protection of protection against HPV infection. In human studies, antibody-induced
gained through vaccination. Results from the HOPE study, measuring neutralisation responses measured in vitro correlate well with the
the community-wide impact of one-dose HPV vaccination, are likely to observed endpoints, including protection against HPV-caused pre-ma­
provide further insight given the high prevalence of HIV in South Africa. lignant lesions or prevention of persistent infection (defined as in­
Lessons learned & the way forward one-dose HPV vaccination studies fections lasting > 6 months) (Schiller et al., 2012). NAbs are, therefore,
IARC India trial and Costa Rica trial (CVT) present long-term follow-up data on a convenient correlates of protection but the minimal protective levels are
substantial number of subjects that received one dose. These ten-year follow-up currently unknown.
results show sustained HPV16/18 antibody levels and > 80% VE for incident A head-to-head comparison study with serum samples collected from
persistent HPV infecton. participants of the PATRICIA (2vHPV Cervarix®) clinical trial in Finland
DoRIS and KEN SHE trials provide further insight into vaccine-induced antibodies
up to 36 months after vaccination with a one-dose regime. These studies are
and the India clinical trial (4vHPV), who had received three doses of the
especially important because they are carried out in countries with the highest HPV vaccines when aged 16–17 years old, showed that 2vHPV recipients had
incidence/attack rate in the world. significantly higher HPV16/18 peak antibody levels than 4vHPV re­
HPV type replacement is currently not an issue as no evidence of genotypes cipients, as determined by a semi-automated high-throughput
competition has been demonstrated. However, surveillance of non-vaccine types
Pseudovirion-Based Neutralisation Assay (PBNA). Furthermore, cross-
remain warranted.
Modelling studies in India, suggesting different scenarios for one-dose including neutralising HPV31/33/45/52/58 Abs were induced by the 2vHPV
stable or waning of protection, based on detection and seropositivity thresholds, Cervarix® significantly more frequently and at higher concentrations
shows one dose strategy to be cost saving and cost effective in most scenarios. than by the 4vHPV (Mariz et al., 2020). Similarly, analysis of serum
To ensure accurate immunobridging responses comparison, samples from samples from 4vHPV recipients and 2vHPV Cervarix® recipients that
prospective trial and historical trials must be from the same sampling timepoint and
tested in the same laboratory with the same serologic validated assay.
were enrolled in the FUTURE and PATRICIA clinical trials and then
Increase need for evidence base data and policies on immunogenicity, protective followed up by the population-based Finnish Maternity Cohort showed
efficacy, and duration of protection of HPV immunisation in immunocompromised that NAb to HPV 16/18 were generally found up to 12 years after
individuals. vaccination, as well as HPV6 antibodies in 2vHPV Cervarix® recipients
One-dose HPV vaccination on cohorts with high-risk HIV acquisition should be
(Mariz et al., 2021). However, 15% of the 4vHPV recipients had no
further studied. However, it should not be a reason to delay adoption of the one-dose
schedule in the general population. detectable HPV18 NAb 2–12 years after vaccination, whereas all cor­
responding 2vHPV recipients had HPV18 NAbs. Cross-neutralising Abs
to HPV31, 33, 45, 52, and 58 were more prevalent in the 2vHPV Cer­
varix® recipients, but similar GMCs to vaccine types were found up to
12 years after vaccination in both vaccine cohorts.
3. Humoral immune responses upon HPV vaccination When comparing the immunogenicity and reactogenicity of the
2vHPV Cervarix® and 4vHPV vaccines in HIV-positive adults recipients
3.1. Immunogenicity of HPV prophylactic vaccines: serology assays and of a three-dose vaccination schedule, anti-HPV18 NAb titres were higher
their use in HPV vaccine evaluation and development: Importance of in the bivalent group compared with the quadrivalent group at seven
international units for reporting immune response and twelve months (Toft et al., 2014). Interestingly, only a moderate
NAb seroconversion (50%) limited to non-vaccine HPV31 in 2vHPV
HPV serology is used to evaluate vaccine-induced antibody duration Cervarix® recipients was observed in this HIV-positive cohort (Faust
and antibody levels. HPV serology can be used to determine the quality et al., 2016). Finally, children with well-controlled HIV infection who
of vaccine-induced antibodies and to report in a standardised manner receive three doses of the 4vHPV vaccine maintain NAbs for at least four
humoral immune responses regardless of serologic assay, laboratory or years (Levin et al., 2017). Although the 2vHPV Cervarix® provides
vaccine used. In all these cases, the availability, relevance, and profi­ slightly broader long-term protection than the 4vHPV in participants of
ciency of internationally standardised tests are important to report HPV the PATRICIA and FUTURE trials, the cross-reactivity induced in HIV-
immunogenicity and validate improvements in serologic HPV assays. positive adults seems, however, diminished in relation to HIV-negative
International standards are required to define an International Unit. cohorts, whereas data on long-term immunity following HPV

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D.-e.-N. Waheed et al. Preventive Medicine Reports 35 (2023) 102368

vaccination in HIV cohorts is scarce. Cervarix® and 4vHPV does not necessarily mean that individuals are
Although NAb titres after vaccination are correlated with protection unprotected, as other factors should be considered, including subopti­
against persistent infection for vaccine HPV types, the correlation is mal sensitivities of current NAbs serological assays. Important advances
weaker for non-vaccine types in 4vHPV recipients (Mariz et al., 2021). It to address these research gaps are underway, including objective com­
is still to be confirmed whether cross-NAb responses are the main ef­ parison between available testing platforms by the use of international
fectors of protection against non-vaccine HPV types. Other Ab-mediated units.
cellular cytotoxicity responses, which are not measured by in vitro
neutralisation assays, may contribute to prevent infection and virus 3.4.2. Cross-protective vaccine-induced neutralising antibodies
clearance (Wang et al., 2018). Vaccination with HPV Virus-Like- A head-to-head comparison between 2vHPV Cervarix® and 9vHPV
Particles VLP also triggers cell-mediated responses (Pinto et al., 2003; provided important insight into the 9vHPV vaccine elicited higher cross-
Stanley, 2006) to T helper epitopes conserved across distinct genotypes protective antibodies against HPV 35 (Arroyo Mühr et al., 2022). This is
(Pinto et al., 2003), which may play some role in both cross-protection specifically important in Africa, where about 10% of cervical cancers
and immunological memory. have been shown to be caused by this genotype. Further research is
In contrast, for considerably more 4vHPV recipients, NAb titres needed to validate and understand the protective value of these anti­
remained below test sensitivity, remarkably for HPV18. This triggered a bodies against persistent infection. This could present an opportunity for
discussion about the impact of the valency (the number of genotypes implementation of these vaccines in countries and populations that are
included in the vaccine) of a given vaccine on the immune response mostly affected by cervical cancer caused by oncogenic genotype
against that vaccine. The immunogenicity data suggest that HPV16 VLP HPV35.
are immunodominant because at similar (2vHPV Cervarix®) or lower
concentrations (4vHPV), these particles induce higher NAb titres than 3.4.3. Feasibility of using first-void urine to assess vaccine status and
HPV18 VLP. Considering that adjuvants are key factors determining the measure impact
balance of antigenic immunodominance (Chen et al., 2021; Maeda et al., Suboptimal vaccine registries in HICs and LMICs could benefit from
2017), the distinct adjuvant systems employed by these vaccines, in the use of FVU sampling as a non-invasive sampling strategy to collect
addition to the valency and antigen concentration, are likely to differ­ impact data. However, there were doubts in regard to the sensitivity of
ently impact the resulting Ab levels. Nevertheless, while NAb titres the sample to detect vaccine-induced antibodies in recipients of one-
induced by each of these vaccines to HPV16 and HPV18 are different, dose schedule. Data presented during the meeting shows that although
their effectiveness levels against corresponding infection seem to be stable, one dose HPV vaccination responses yields lower antibody titers
comparable. in serum. While further validation and optimization of this strategy is
needed, promising results, including the detection of antibody after
3.3. Current status of using urine samples to monitor HPV vaccination natural infection in urine and a very good correlation between serum
status and FVU antibodies titers has been reported, making this sampling
strategy a very promising asset for HPV vaccine effectiveness assessment
First-void urine (FVU), or the initial stream of urine, captures im­ worldwide.
purities lining the urethra opening. These impurities include tran­ Lessons learned & the way forward.
sudated Abs and biomarker-containing mucus and debris from humoral immune responses upon HPV vaccination
exfoliated cells originating from the female genital tract. As it is a non- The availability of international standards is relevant, as it will facilitate HPV
invasive sample, which can be obtained at home, it is an interesting immunogenicity reporting and accurate data interpretation across labs and testing
option to reach non-attendees of the cervical cancer screening pro­ batches.
VLPs are highly immunogenic, resulting in high-affinity Abs. Due to intramuscular
gramme (Pattyn et al., 2019). Several studies have demonstrated that
administration with adjuvant, the resulting Abs are of better quality than Abs
first-void urine is a suitable sample to detect HPV DNA and vaccine- resulting from natural infection.
induced HPV Abs originating from female genital tract secretions are Humoral immune responses following HPV vaccination reach a plateau at 24
detectable in FVU as well (Arbyn et al., 2018; Pathak et al., 2014). This months, irrespective of the number of doses administered. As such, it is essential to
analyze data from studies with a minimum follow-up period of 24 months in order to
presents an opportunity for non-invasive sampling to monitor HPV Ab
accurately compare results across studies.
status in women participating in large epidemiological studies and HPV First-void urine sampling is a non-invasive, home-based sampling method that
vaccine trials (Pattyn et al., 2019, 2020; Van Keer et al., 2019). The allows the detection of HPV-specific antibodies.
simultaneous assessment of both HPV infection and immunogenicity on International Standards for 9 HPV vaccine genotypes need to be anchored, and for
a non-invasive, readily obtained sample is particularly attractive. instance, peer reviewers should ask for international units when reviewing
manuscripts.
Paired FVU and serum samples from female volunteers who partic­
ipated in a 9vHPV trial (HPV V503-004 study) were collected before
vaccination (month 0), one month after the third dose (month 7), and
approximately three years after the third dose (month 43) (manuscript
under preparation). HPV-specific antibody concentrations in FVU were
detected in 0–16% at month 0, 95%–100% at month 7, and 84%–100% 4. Ethics approval
at month 43. In addition, results show significant spearman correlations
between HPV-antibody titres of paired FVU and serum samples (Month Not applicable.
0 rs = 0.52, Month 7 rs = 0.69, Month 43 rs = 0.80). In conclusion, HIV
Abs can also be detected in urine, which might make FVU a valid sample 5. Consent to participate
in LMICs with a high HIV burden. However, due to biological differences
in the genital tract, FVU is probably not an appropriate sample for HPV Not applicable.
DNA or antibody detection in men.
6. Consent for publication
3.4. Panel discussion on humoral immune responses
HPV Prevention and Control Board meetings are invitation-only
3.4.1. Optimisation of current antibody neutralization assays meetings. All participants accepted the invitation and attended the
An important remark was made in regard to the fact of not detecting meeting out of their free will. The HPV Prevention and Control Board
neutralising antibodies 12 years post-vaccination in recipients of 2vHPV asked the participants to fill out a ‘consent form’, agreeing that the

7
D.-e.-N. Waheed et al. Preventive Medicine Reports 35 (2023) 102368

videos and photos of the meetings can be published online. The speakers References
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The HPV Prevention and Control Board is supported by in kind
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Declaration of Competing Interest Maeda, D.L.N.F., Batista, M.T., Pereira, L.R., de Jesus Cintra, M., Amorim, J.H., Mathias-
Santos, C., Pereira, S.A., Boscardin, S.B., Silva, S.D.R., Faquim-Mauro, E.L.,
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The authors declare that they have no known competing financial 2017. Adjuvant-Mediated Epitope Specificity and Enhanced Neutralizing Activity of
interests or personal relationships that could have appeared to influence Antibodies Targeting Dengue Virus Envelope Protein. Front. Immunol. 8.
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