HPV Vaccines: What We Know and What We Should Expect Laura Koutsky, PhD Professor of Epidemiology...
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Transcript of HPV Vaccines: What We Know and What We Should Expect Laura Koutsky, PhD Professor of Epidemiology...
HPV Vaccines: What We Know and What We
Should Expect
Laura Koutsky, PhD
Professor of Epidemiology
University of Washington
Seattle, WA
Summary of Cervical Cancer Prevention Options
• Current optionsCurrent options– AbstinenceAbstinence– Lifelong mutual monogamy Lifelong mutual monogamy – Screening (followed by diagnosis and treatment)Screening (followed by diagnosis and treatment)
• HPV DNA or Pap testingHPV DNA or Pap testing• Both HPV DNA and Pap testingBoth HPV DNA and Pap testing
• Future optionsFuture options– Screening or triage by more accurate and less costly Screening or triage by more accurate and less costly
biomarkers (e.g., p16biomarkers (e.g., p16INK4a INK4a protein, DNA methylation markers)protein, DNA methylation markers)– Prophylactic and therapeutic vaccinesProphylactic and therapeutic vaccines
HPV L1 VLP Vaccine Synthesis
Yeast CellYeast Cell
L1 L1 gene gene
on HPV on HPV DNADNA
L1 gene inserted L1 gene inserted into genome of into genome of
yeast cellyeast cell
Yeast cell DNAYeast cell DNA
mRNAmRNAtRNAtRNA
rRNArRNA
TranscriptionTranscription
TranslationTranslation
Capsid proteinsCapsid proteins
Empty viral capsids
Elicits Elicits immune immune
response in response in hosthost
HPV L1 Virus-Like Particle (protein from the L1 gene of HPV)
Results from Two Randomized Clinical Trials of Young Women (~15 to 25 Years of Age) using HPV 16 or HPV 16 and 18 L1 VLP Vaccines
Merck GSK Vaccine Placebo VE (95% CI) Vaccine Placebo VE (95%
CI)
768 765 401 397 Endpoint: Persistent HPV 16 0 41 100 (90,100) HPV 16 or 18 0 10 100 (20,100)
HPV16-CIN 0 9
Merck Vaccine: HPV16 L1 VLP expressed in yeast (NEJM 2002;347:1645-51) GSK Vaccine: HPV16 & 18 L1 VLP expressed in baculovirus system (presented at EUROGIN Meeting in Paris April, 2003)
Results from Two Randomized Clinical Trials of HPV L1 VLP Vaccines (cont.)
Both Merck and GSK trials showed:– High efficacy for preventing HPV infection
– High levels of immunogenicity• >99% of vaccinees seroconverted• Antibody titers considerably higher than
observed in natural infection
– Generally safe and tolerable
Anti-HPV 16 RIA Following Vaccination (Merck Trial) GMTs (mMU/mL) With 95% CIs
HPV 16 10 gHPV 16 20 gHPV 16 40 gHPV 16 80 g
Time (Months)
Ge
om
etr
ic M
ean
Tite
r (m
MU
/mL
)
0 3 7 12 18 241
10
100
1000
GMT
95% CIAnti-HPV 16 in women with ongoing/previous HPV 16 infection
High titers persist through month 36
Tolerability of Vaccination (Merck Trial)
Subjects with follow-up
With vaccine-related AEsInjection-site AEsSystemic AEs
Discontinuations due to an AE
With serious AEs
With serious vaccine-related AEs
HPV 16 Vaccine
(N=1194)
1130
1011 975 470
4
4
0
(95)
(90) (86) (42)
(<1)
(<1)
(0)
n (%)1150
1007 947 500
5
3
0
(96)
(88) (82) (44)
(<1)
(<1)
(0)
Placebo(N=1198)
n (%)
Other HPV L1 VLP Vaccine Findings
• Cannot cause HPV infection– Vaccine only contains one protein from the
virus (L1 protein)
• HPV L1 protein is not a human carcinogen
• HPV L1 VLPs appear to elicit both B cell and T cell responses
• HPV antibody responses to L1 VLPs appear to be mostly type-specific
Detection of HPV Types in Cervix Cancers from Different Regions of the World
from Clifford Br J Cancer 2003;88:63
Europe
56
17.2
0.8
0.5
0.5
2.2
2.94.2
4.416
18
45
31
33
58
52
35
Others
Latin America
51.7
10.6
5.5
7
4
2.9
3.3
213
16
18
45
31
33
58
52
35
Others
Europe
56
17.2
4.4
0.8
0.5
0.5
13.5
2.94.2
16
18
45
31
33
58
52
35
Others
Africa
50.2
14.1
7.9
2.6
3.1
1.6
1.6
1.417.5
16
18
45
31
33
58
52
35
Others
Asia
43.4
15.3
4.5
2
3.4
5.4
4.2
1
20.8
16
18
45
31
33
58
52
35
Others
54.9
22.1
0.2
0.6
0.4
11.4
3.33.93.2
16
18
45
31
33
58
52
35
Others
HPV Types
Ongoing HPV L1 Vaccine Trials
• Phase II trial of Merck tetravalent HPV 6, 11, 16, and 18 vaccine near completion – high antibody titers for each HPV type
• International phase III trial of Merck tetravalent HPV 6, 11, 16, and 18 vaccine has begun – Potential elimination of up to:
• 70% of invasive cervical cancers• 60% of high grade cervical intraepithelial lesions• 90% of genital warts and recurrent respiratory papillomatosis
• GSK Phase III trial of bivalent HPV 16 and 18 vaccine to begin soon
HPV L1 VLP Vaccine Research
• Prevention of CIN2-3 and anogenital warts• Duration of protection • Gender differences in vaccine efficacy • Therapeutic potential of HPV VLP vaccines for post-infection
protection • Increasing number of HPV types prevented• Potential for “replacement” lesions• Cost–effective approaches to screening and vaccinating
– increase screening interval– improve accuracy of screening test
• Reduction in incidence of cervical and other anogenital cancers, head and neck cancers and RRP
Future HPV Immunization Programs Implementation Issues
• Potential target populations– 9 -12 years of age – Adolescents and young adults
• Protection in men– Data on HPV vaccine efficacy in men not yet available– Only vaccinating women might be a good option in some
communities
• Societal acceptance of vaccines to prevent sexually transmitted infections– Awareness of HPV consequences and ubiquity – Anti-cancer vaccine
Potential Impact of HPV 6, 11, 16, and 18 Vaccine on STD Control
• Reduce number of genital wart visits– Later or less frequent detection of other STDs
• Reduce number of women requiring referral to colposcopy, biopsy and treatment
• Increase demand for information on HPV and HPV vaccines– Vaccine is prophylactic not therapeutic– Vaccine does not prevent all HPVs or other
STDs/HIV– Pap screening still important
Take Home Messages• A prophylactic vaccine to prevent HPV 6, 11, 16, and 18
infections and related-neoplasms is likely to be available within 4 to 6 years
– The promise of such a vaccine will be realized only if immunization programs achieve wide coverage
• 2nd generation vaccines that prevent infection by additional oncogenic HPV types are under development
• Screening to detect and treat lesions in women who were infected prior to vaccination or infected with HPV types not covered by the vaccine will continue
– More accurate and less costly screening tests are being developed
• Public health experts must begin thinking about the use of prophylactic HPV vaccines in their communities
Collaborators• University of Washington
• Akhila Balasubramanian
• Qinghua Feng
• Tiffany Harris (Albert Einstein)
• King Holmes
• James Hughes
• Jane Kuypers
• Nancy Kiviat
• Shu-Kuang Lee
• Connie Mao
• Leslie Miller
• Bethany Weaver
• Noel Weiss
• Rachel Winer
• Long Fu Xi
• Duke University• Shalini Kulasingam
• Evan Myers
• Fred Hutchinson Cancer Research Center• Denise Galloway
• Jody Carter
• Merck Research Laboratories• Eliav Barr
• Kathrin Jansen
• University of New Mexico• Cosette Wheeler