Document text
Introduction to policy considerations:
Reduced number of HPV vaccine doses
Lauri Markowitz, MD
Co-Lead, HPV Vaccines Work Group
Division of Viral Diseases
Advisory Committee on Immunization Practices
October 24, 2024National Center for Immunization & Respiratory Diseases
▪Brief introduction to human papillomavirus (HPV)
▪HPV vaccines and vaccination recommendations in the United States
▪Overview of data on vaccination with a reduced number of doses
▪World Health Organization recommendations and international landscape Outline
2
Introduction
3
18 years since first HPV vaccine licensure
▪High vaccine efficacy in clinical trials
▪High population impact in real world settings
▪Strong herd effects of vaccination programs
▪Implementation challenges in many countries
▪Lag in vaccine introduction in low - and middle -income counties
4
▪Double -stranded DNA virus (8 kb circular genome)
▪> 200 closely related types
•L1 is major capsid protein
•Sequence of L1 gene determines type
▪12 types classified as high -risk (oncogenic)
•HPV 16 and HPV 18 responsible for most HPV -attributable cancer
▪Low -risk HPV types
•HPV 6 and HPV 11 cause most anogenital warts and recurrent respiratory
papillomatosis
▪Most common sexually transmitted infection
•~ 13 million persons in the United States become infected with a disease -
causing HPV type each year
•Over 90% become undetectable in 2 years Human papillomaviruses
5HPVCervical
Oropha
ryngea l
Anal
PenileVulvarVaginal
HPV-attributable cancer
Wright and Schiffman. N Engl J Med 2003
HPV infection causes cervical cancer (and other cancers)
after years to decades
6
HPV -associated and estimated HPV -attributable cancer
cases per year, United States, 2017 –2021
Cancer siteNumber of HPV -
associated
cancersPercentage
probably caused
by any HPV typeEstimated number probably caused
by any HPV type*
Female Male Both sexes
Cervix 11,959 91% 10,800 - 10,800
Vagina 898 75% 700 - 700
Vulva 4,418 69% 2,900 - 2,900
Penis 1,381 63% - 900 900
Anus** 7,854 91% 5,000 2,200 7,200
Oropharynx 21,474 70% 2,300 12,900 15,200
TOTAL 47,984 79% 21,800 16,000 37,800
*Estimates were rounded to the nearest 100. Estimated counts might not sum to total because of rounding.
**Includes anal and rectal squamous cell carcinomas
Sources: Cancers Linked With HPV Each Year | Cancer | CDC and http://www.cdc.gov/cancer/dataviz 7
HPV vaccines and recommendations
8
▪Virus -like particle (VLP) vaccines
▪L1 major capsid proteins self -assemble into VLPs
▪High efficacy with durable protection Available prophylactic HPV vaccines
HPV VLP
9
HPV vaccines licensed in the United States
Vaccine and
brand nameBivalent (2vHPV)
CervarixQuadrivalent (4vHPV)
Gardasil9-valent (9vHPV)
Gardasil 9
Types 16, 18 16, 18, 6, 11 16, 18, 6, 11
31, 33, 45, 52, 58
Prevents cancer cancer
anogenital wartscancer
anogenital warts
Adjuvant AS04
500 µg aluminum hydroxide
50 µg 3-O-desacyl -4’
monophosphoryl lipid AAAHS
225 µg amorphous aluminum
hydroxyphosphate sulfateAAHS
500 µg amorphous aluminum
hydroxyphosphate sulfate
Year licensed 2009 2006 2014
Manufacturer GlaxoSmithKline Merck & Co. Merck & Co.
HPV 16 and 18 are oncogenic types that cause most HPV -attributable cancers; HPV 31,33,45,52,58 are oncogenic types that cause ab out 12% of
HPV -attributable cancers; HPV 6,11 cause most anogenital warts and recurrent respiratory papillomatosis 10
HPV vaccines licensed in the United States
Vaccine and
brand nameBivalent (2vHPV)
CervarixQuadrivalent (4vHPV)
Gardasil9-valent (9vHPV)
Gardasil 9
Types 16, 18 16, 18, 6, 11 16, 18, 6, 11
31, 33, 45, 52, 58
Prevents cancer cancer
anogenital wartscancer
anogenital warts
Adjuvant AS04
500 µg aluminum hydroxide
50 µg 3-O-desacyl -4’
monophosphoryl lipid AAAHS
225 µg amorphous aluminum
hydroxyphosphate sulfateAAHS
500 µg amorphous aluminum
hydroxyphosphate sulfate
Year licensed 2009 2006 2014
Manufacturer GlaxoSmithKline Merck & Co. Merck & Co.
11After the end of 2016, only 9vHPV available in the United States
Efficacy and immunogenicity trials for initial licensure
of HPV vaccines, 3 -dose schedules (0, 1 -2, 6 months)
Randomized controlled efficacy trials
in ~15 –26-year -old women
Endpoints:
- cervical precancers and external
genital lesions
Per protocol analyses:
- efficacy >96%
- seroconversion ~ 100 %
Immunobridging trials in
9–15-year -olds
Licensure based on non -
inferior antibody response
compared with women in
efficacy trials
Future II Study Group, NEJM 2007; Garland, et al. NEJM 2007; Paavonen, et al. Lancet 2007
Quadrivalent vaccine trials had other endpoints including, vulvar, vaginal precancers and genital warts12
2006 2011 2016 2019Females
Routine :11or12years ,
can be started at age 9
Catch -up:through 26years
3-dose scheduleMales
Routine :11or12years ,
can be started at age 9
Catch -up:through 21years
3-dose schedule2-dose schedule
iffirst dose age
<15 yearsShared clinical decision -
making : some adults
27 through 45 years
Catch -up:harmonized
through age 26 yearsEvolution ofHPV vaccination recommendations –
United States
13
Current HPV vaccination recommendations, United States
Recommendations of the Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices
https://www.cdc.gov/vaccines/hcp/acip -recs/vacc -specific/hpv.htmlRoutine vaccination
▪Age 11 or 12 years
▪Can be started at age 9 years
Catch -up vaccination
▪Through age 26 years
Shared clinical decision -making
▪Age 27 –45 yearsNumber of doses
2 doses (0, 6 -12 months)
if starting series before 15th birthday
3 doses (0,1-2, 6 months)
if starting series on or after 15th birthday or
if immunocompromising condition
14
▪Post hoc analyses of a 3 -dose randomized trial (2vHPV vs control vaccine)
-Not all participants completed 3 -dose schedule
-Efficacy against HPV16/18 infection similar after 3, 2, 1 doses
▪Immunobridging trials
-2 doses in 9–14-year -olds vs 3 doses in young adult women
-Seroconversion and GMTs were non -inferior in 2 -dose groupHow did we get to 2 doses?
15
J Natl Cancer Inst 2011
GMT ( mMU /mL))Data from 9vHPV
immunobridging trial
Similar findings for 2vHPV and 4vHPV: Romanowski, Hum Vaccin Immunother
2016; Puthanakit , JID 2016; Lazcano -Ponce, Vaccine 2014; Dobson, JAMA 2013;
Hernández -Ávila, Hum Vaccin Immunother 2016; Iversen et al. JAMA 2017HPV type
Iversen et al. JAMA 20172 doses (0,6 or 0,12 months) in
adolescents (9 -14 years)
compared with
3 doses (0,2,6 months)
in women (16 -26 years)
16
10100100010000
6 11 16 18 31 33 45 52 58Girls (0,6) Women (0,2,6)
Licensure and recommendations for a 2 -dose HPV
vaccination schedule
Manufacturers submitted supplemental applications for 2 doses in 9 –14-yr-olds
FDA and other regulatory authorities approved
WHO, ACIP , other advisory groups recommended a 2 -dose series at 9 –14 years
17
2016 2014
Evidence on single -dose vaccination
18
▪Stimulated by same studies that led to 2 -dose schedules
▪Immunobridging trials not possible for single -dose
-Single dose results in lower antibody titers than 2 or 3 doses
-Basis of protection after HPV vaccination thought to be neutralizing antibody
-No established minimum antibody threshold for protectionSingle -dose HPV vaccination – initial interest
19
Trial
Girls 12–16 years old
(n=20,300)
Bivalent
(n=10,150)9-valent
(n=10,150)
Active Follow -up
Cervical cells, blood, urine at M12, M18, M24, M30, M36,
M42, M48, M54, M60M0: Randomized to vaccine
M6: Randomized to dosing
schedule
1 Dose 2 Doses 1 Dose 2 DosesEpidemiologic Surveys
(unvaccinated)
HPV infection status
M0 and M6
HPV vaccine
ESCUDDO, Costa Rica (data available 2025)
▪Randomized trial to evaluate non -inferiority of one vs two doses of 2vHPV (Cervarix) and 9vHPV
(Gardasil 9) for prevention of new cervical HPV16/18 infections that persist at least 6 months
▪Evaluate one dose compared to zero doses
ClinicalTrials.gov: NCT03180034
▪Studies that initially provided data had further encouraging data
▪Recognition of a global HPV vaccine supply/demand imbalance
▪Additional studies were planned and conducted
▪Review of data led to revised World Health Organization recommendations
including, “as an off -label option, a single -dose schedule can be used in girls
and boys aged 9 –20 years.”Single -dose HPV vaccination – increasing interest
21
Trial/country Evidence VaccineAge ( yrs) at
vaccinationDescription
CVT
Costa RicaEfficacy/
Immunogenicity2vHPV 18–25 Post -hoc analyses
Original trial: randomized to 3 doses or
control, but analyzed as 1 -, 2-, 3-dose groups
IARC -India
IndiaEfficacy/
Immunogenicity4vHPV 10–18 Post -hoc analyses
Original trial: randomized to 2 or 3 doses
but analyzed as 1 -, 2-, 3-dose groups
KEN SHE
KenyaEfficacy 2vHPV
9vHPV15–20 Randomized trial
1 dose 2vHPV, 9vHPV or MCV
DoRIS
TanzaniaImmunogenicity 2vHPV
9vHPV9–14 Randomized trial
1-, 2-, 3-dose groups
22 2vHPV, Cervarix; 9vHPV, Gardasil 9; CVT, Costa Rica Vaccine Trial; IARC, International Agency for Research on CancerTrials with data on single -dose HPV vaccination
considered by the World Health Organization in 2022
23Costa Rica Vaccine Trial (CVT)
Protection against prevalent HPV after 2vHPV, through 11 years
Doses Number Prevalent 16/18 HPV
% (95% CI)Vaccine efficacy
% (95% CI)
3 doses 1365 2.0 (1.3–2.8) 80.0% (70.7 –87.0)
2 doses 62 1.6 (0.1–7.7) 83.8% (19.5 –99.2)
1 dose 112 1.8 (0.3–5.8) 82.1% (40.2 –97.0)
Unvaccinated 1783 10.0 (8.7 –11.4) Reference▪Post -hoc analysis of RCT: females vaccinated at age 18 –25 years
▪Randomized to receive 3 doses of 2vHPV or control vaccine
Kreimer AR, et al. J Natl Cancer Inst 2020 23
Costa Rica Vaccine Trial (CVT)
HPV 16 antibody after 1, 2 or 3 doses of 2vHPV, through 11 years
Antibody by VLP -based ELISA at the NCI HPV Immunology Laboratory
Kreimer AR, et al. J Natl Cancer Inst 2020•Stable HPV 16 and 18
antibody levels through 11
years post vaccination with
all dosing schedules
•1 dose levels at least 10 -fold
above level at enrollment
among unvaccinated
Unvaccinated
24
IARC, International Agency for Research on Cancer
Sankaranarayanan R, et al. Lancet Oncol 2016IARC -India Trial: provides data on immunogenicity
and efficacy of 1, 2 and 3 doses of 4vHPV (Gardasil)
2 dose
group
25Randomized trial
design lost and
analyzed as
observational
cohortCluster randomized trial
2 vs 3 doses of 4vHPV in 10 –18 year -old
unmarried girls, initiated Sept 2009
Loss of randomization due to order in April 2010 by
Ministry of Health to stop HPV vaccination in research studies2 dose
Group
(0,6 months)3 dose
Group
(0,2,6 months)
251 dose2 doses
0, 2 months3 doses 2 doses
0, >6 months
IARC -India Trial
Protection after 1, 2 or 3 doses of 4vHPV, through 10 years
Doses NumberPersistent HPV16/18 Vaccine efficacy
% (95% CI)Events %
3 doses 1460 1 0.07 93.3% (77.5 –99.9 )
2 doses 1452 1 0.07 93.1% (77.3 –99.8 )
1 dose 2135 1 0.05 95.4% (85.0 –99.9 )
Control 1260 32 2.54 Reference
26Unvaccinated women age -matched to married vaccinated participants recruited as controls
Persistent infection defined as the same HPV type detected in consecutive samples at least 10 months apart
VE adjusted for background HPV infection frequency, time between date of marriage and first cervical specimen collection, and number of cervical specimens per participant
26IARC, International Agency for Research on Cancer
Basu P, et al. Lancet Oncol 2021; published correction in Lancet Oncol. 2022 Jan;23(1):e16. IPVC2023 Abstract O177 / #862 . ▪Post hoc analysis of randomized trial: females vaccinated at age 10 –18 years
▪Randomized to receive 2 or 3 doses 4 vHPV
Sexually active females
aged 15 -20 years
2275 randomized
2vHPV
1 dose9vHPV
1 doseMeningococcal
1 dose▪Double -blind, RCT
▪Sexually active females aged 15 -20 years
▪Trial groups
▪2vHPV (Cervarix)
▪9vHPV (Gardasil 9)
▪Meningococcal (d elayed HPV vaccination)
▪Primary objectives
▪Efficacy in preventing incident persistent infection*
–HPV-16/18
–HPV-16/18/31/33/45/52/58 KEN SHE Trial - Kenya
Barnabas R, et al. NEJM Evidence 2022 *Defined as vaccine -type specific HPV detected at two consecutive time points no less than 4 months apart
27
KEN SHE: RCT of single -dose HPV vaccination
Incident persistent 16/18 infections and vaccine efficacy
18 months 36 months
Vaccine NIncident
persistent
HPV 16/18Incidence/
100 PYVE %
(95% CI)Incident
persistent
HPV 16/18Incidence/
100 PYVE %
(95% CI
9vHPV 496 1 0.1797.5%
(81.7 –99.7)1 0.0898.8%
(91.3 –99.8)
2vHPV 489 1 0.1797.5%
(81.6 –99.72 0.1697.5%
(90.0 –99.4)
Meningococcal 473 36 6.83 Reference 72 6.70 Reference▪1458 evaluated f or efficacy in mITT cohort
28 Barnabas R, et al. Nature Medicine 2023Enrollment criteria: 1 -5 lifetime partners; HIV negative; enrollment between December 2018 and June 2021
MCV, meningococcal vaccine; mITT , modified intention to treat: HPV 16/18 HPV DNA negative (external genital and
cervical swabs) at enrollment and month 3 (self -collected vaginal swab) and HPV antibody negative at enrollment
PY, person years
Barnabas R, et al. NEJM Evidence 2022
Through three years after vaccination , 1-dose HPV vaccine efficacy remained high
Barnabas R, et al. Nature Medicine 20239v VE= 99% for HPV 16/18 (95% CI: 91 – 100%)
2v VE= 98% for HPV 16/18 (95% CI: 90 – 99%)
VE=96% for HPV 16/18/31/33/45/52/58
(95% CI: 89 – 98%)
29KEN SHE: RCT of single -dose HPV vaccination
DoRIS - Tanzania
▪Dose Reduction Immunobridging & Safety Study
▪Randomized, open label trial in girls aged 9 -14 years
▪1, 2, 3 doses of 2vHPV (Cervarix) or 9vHPV (Gardasil 9)
▪Objectives – demonstrate noninferiority
–HPV 16 and 18 antibody response after 1 vs 2 or 3 doses of same vaccine
–HPV 16 and 18 GMCs: 1 dose in DoRIS vs 1 dose in studies that evaluated efficacy
GMC, geometric mean concentration30Girls aged 9 -14 years
N=930
2vHPV
1 dose2vHPV
2 doses2vHPV
3 doses9vHPV
1 dose9vHPV
2 doses9vHPV
3 doses
DoRIS conclusions
31
Watson -Jones D, et al. Lancet Global Health 2022
DoRIS conclusions
▪Seropositivity >97. 8%after vaccination for all vaccine groups
32 Watson -Jones D, et al. Lancet Global Health 2022
DoRIS conclusions
▪Seropositivity >97.8% after vaccination for all vaccine groups
▪Antibody levels lower after 1 dose compared with 2 or 3 doses
•Kinetics, with plateau, similar for all doses
33
Watson -Jones D, et al. Lancet Global Health 2022 9vHPV vaccine groups
DoRIS conclusions
▪Seropositivity >97. 8%after vaccination for all vaccine groups
▪Antibody levels lower after 1 dose compared with 2 or 3 doses
•Kinetics, with plateau, similar for all doses
▪ Avidity for each HPV type was similar for 3, 2 and 1 doses for both vaccines
34 Watson -Jones D, et al. Lancet Global Health 2022
DoRIS conclusions
▪Seropositivity >97.8% after vaccination for all vaccine groups
▪Antibody levels lower after 1 dose compared with 2 or 3 doses
•Kinetics, with plateau, similar for all doses
▪Avidity for each HPV type was similar for 3, 2 and 1 doses for both vaccines .
▪Immunobridging : 1-dose responses were non -inferior in DoRIS (9-14 year -olds)
compared with those among women in studies where 1 -dose efficacy observed
35
Lancet Global Health 2024
HPV 16 and 18 antibodies measured by ELISA at Frederick National Laboratory for Cancer Research HPV Immunology Laboratory, USA
Study/
countryEvidence VaccineAge ( yrs) at
vaccinationDescription
HOPE
South AfricaImpact/
Effectiveness2vHPV 15–16 1 dose as catch -up in grade 10. Baseline and cross
sectional prevalence surveys; includes WLWH
Thailand Impact
Thailand Effectiveness 2vHPV Grade 8
age <15 yrs1 or 2 doses, by province; Baseline and post -
vaccination cross sectional prevalence surveys
HANDS
The GambiaImmunogenicity 9vHPV 4–8, 9–14
15–26Randomized trial of 1 or 2 doses vs
3 doses in 15 –26-year -olds
Primavera
Costa RicaImmunogenicity 2vHPV
9vHPV9–14
18–251 dose
3 doses
PRISMA
Costa RicaEfficacy 2vHPV
4vHPV
9vHPV18–30 Randomized trial of 1 dose of three different HPV
vaccines vs unvaccinated
ESCUDDO
Costa RicaEfficacy/
Immunogenicity2vHPV
9vHPV12–16 Randomized trial of 1 vs 2 dosesAdditional studies evaluating single -dose HPV
vaccination, data forthcoming
36 2vHPV, Cervarix; 9vHPV, Gardasil 9; WLWH, women living with HIV; RCT, randomized controlled trial. All studies conducted among girls/women
Study/
countryEvidence VaccineAge ( yrs) at
vaccination Data expected
CVT
Costa RicaEfficacy/
Immunogenicity2vHPV 12–16 14-, 16- and 20 -year data
IARC -India
India Efficacy/
Immunogenicity4vHPV 10-18 12-year data and further
DoRIS
TanzaniaImmunogenicity 2vHPV
9vHPV9-14 36- and 60 -month dataAdditional data from studies reviewed today
372vHPV, Cervarix; 9vHPV, Gardasil 9
WLWH, women living with HIV; RCT, randomized controlled trial. All studies conducted among girls/women
▪Studies of single -dose also provide data on a 2 -dose schedule
•Studies with a 2 -dose group (0, 6 months)
–CVT (2vHPV): 18 –25-year -olds
–IARC -India (4vHPV): 10 –18-year -olds
▪Immunogenicity trial of 2 vs 3 doses of 9vHPV*
•U.S. study in 15 –26-year -olds
•Ongoing - interim data published Two HPV vaccine doses for persons aged >15 years
38 *Berenson A, et al. NEJM Evidence 2024
2022 World Health Organization
recommendations and global landscape
WHO recommendations forHPV vaccination
December 2022:
Evidence supports a 2-dose schedule from
age 9years and for allolder agegroups for
which HPV vaccines arelicensed.
Asanoff-label option, asingle -dose
schedule can beused ingirls and boys
aged 9–20years.
40
Date: October 2024 41
Doses -intervalNo. of
countries
1 dose 58
2 doses (12 months) 5
2 doses (6 months 76
Not yet introduced 50
Unknown schedule 5Recommended HPV vaccine schedules in 9‒14 -year -olds,
by country
▪Some of the first countries to change to a routine single -dose schedule
–England, Ireland, Australia
▪Change from a 3 -dose to a 2 -dose schedule for persons ages >14 years
–Netherlands and Sweden
▪Single -dose recommendations by regional advisory groups
–PAHO in 2023 and AFRO in 2024Policy changes since updated WHO HPV vaccination
recommendations in 2022
42PAHO Technical Advisory Group recommends countries of the Americas to use single -dose HPV vaccine schedule | OPS/OMS | Organisation panaméricaine de la santé
Africa immunization advisory group urges single -dose HPV vaccine adoption to advance vaccination efforts | WHO | Regional Office for Africa
▪Longer term efficacy and immunogenicity
▪Protection at sites other than the cervix
▪Efficacy and immunogenicity in males*
▪Efficacy and immunogenicity in immunocompromised persons
▪Efficacy and immunogenicity in older age groupsOutstanding questions for single -dose vaccination ?
Additional data expected over the next year will
address some of these questions
* Data available from a small immunogenicity trial in 11 –12-year -old girls and boys: Zeng et al. Pediatrics 2023 43
▪Plan to conduct two prospective clinical trials, one in females (16 -26 years)
and one in males (ages 16 -26 years).
▪These randomized, double -blind, multi -year clinical trials will examine the
short and long -term efficacy and immunogenicity of a single -dose of Gardasil 9
versus the currently approved three -dose regimen.
▪Merck is in discussions with FDA about the protocols and the timeline.
Merck Announces Plans to Conduct Clinical Trials of a Novel Investigational Multi -Valent Human Papillomavirus (HPV)
Vaccine and Single -Dose Regimen for GARDASIL®9 Announcement from Merck, March 2024
44
▪HPV vaccines were first studied and licensed in a 3 -dose schedule in persons
aged 9 –26 years and later in a 2 -dose schedule in persons aged 9 –14 years.
▪Data are available on single -dose HPV vaccination, including from a RCT with 3
years of follow -up, showing high efficacy against incident persistent infection.
▪Long term follow -up suggests protection for >10 years with a single dose.
▪WHO 2022 updated recommendations: 2 doses for persons aged 9 years and
older, with option for single -dose HPV vaccination through age 20 years,
except those immunocompromised.
▪Countries are considering new or updated HPV vaccination policy and an
increasing number have recommended single -dose HPV vaccination.
▪Further data on 1 and 2 doses will be available over the next year. Summary
45
▪Review further evidence
•1- and 2 -dose schedules
•Modeling data
•Other relevant data
▪Evaluate evidence using GRADE and evaluate policy questions using the
Evidence to Recommendations framework
•Should a 1 -dose schedule be recommended in some age groups?
•Should a 2 -dose schedule, instead of a 3 -dose schedule, be recommended in
some age groups older than 9 –14 years?Next steps for ACIP HPV Vaccines Work Group
46
What questions does ACIP have regarding the policy
questions being addressed? Questions for ACIP
47
For more information, contact CDC
1-800-CDC-INFO (232 -4636)
TTY: 1 -888-232-6348 www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the
official position of the Centers for Disease Control and Prevention.Thank You