How HPV vaccines can turn the tide：如何HPV疫苗可以力挽狂澜

1、How HPV Vaccines can turn the tideDr. S. KukrejaHead, Department of Pediatrics Max Super speciality Hospital New Delhi 110092 natural immune response after HPV infection 80 % of women acquire HPV infection in their life time. Most HPV infections of cervix are asymptomatic. Most women ( 90% )clear th

2、e infection. 5-10 % will not clear it and will lead to persistent infection. Only 50%develop serum antibody to HPV after natural infection very low Ab levels Significant proportion of women do not develop any antibody after HPV infection. minimal or no immune response following HPV INFECTION . This

3、immune response being sufficient to clear most ongoing infection but does not appear to prevent subsequent infectionAttack rate of HPV infection 1 in women who previously got infected and cleared the HPV infection 2 and HPV nave women AR in Both groups is very similar. Most women continue to be susc

4、eptible to re infection with HPV infection ( even with the same type) The HPV Virus has evolved several mechanisms to minimize or prevent exposure to the hosts immune system, enabling it to avoid the immune response.HPV cervical infection A Sophisticated Immune Evasion Mechanism1-41.Stanley M. Vacci

5、ne 2006; 24: S106-13, 2.Tindle, Nat Rev Cancer 2002; 2, 59, 3.Stanley M. Vaccine 2006; 24: S16-22, 4. Stanley M. HPV Today 2007; 11: 1-16Local imucosal lnfection1-4Infects the epithelium through micro abrasions1-4No viremiaNo systemic infectionHPV not exposed to immune system No mounting of Ab respo

6、nse How does Vaccine work ? HPV antigen is injected( instead of mucosal exposure in natural infection ) Immune response induced by HPV vaccination is differentGeneration of an immune response that improves on natural immunity Vaccination aims to prevent HPV infection by inducing high1 and sustained

7、serum neutralizing antibody levels in all vaccinees2Natural immunity does not provide this response to infection35Neutralizing antibody levelsYearsEffective antibody response after vaccinationAntibody level following natural infectionDiagrammatic representation: characteristics of an effective HPV v

8、accineVaccinationSuboptimal antibody response after vaccination 1. Stanley M, et al. Vaccine 2006; 24(Suppl 3):S106S113; 2. WHO Department of Immunization, Vaccines and Biologicals, 2007; 3. Carter JJ, et al. J Infect Dis 2000; 181:19111919; 4. Viscidi RP, et al. Clin Diagn Lab Immunol 1997; 4:12212

9、6; 5. Ho GY, et al. Cancer Epidemiol Biomarkers Prev 2004; 13:110116.1. Parr EL et al. J Virol 1997;71(11):8109-15, 2. Nardelli-Haefliger D et al. J Natl Cancer Inst 2003;95(15):1128-37, 3. Schiller JT et al. Nat Rev Microbiol 2004;2(4):343-7, 4. Poncelet et al. ESPID, Porto, Portugal 2007; Abstract

10、 37, session ES2, 5. Stanley M. HPV Today 2007; 11: 1-16, 6. Einstein M, Cancer Immunol Immunother 2007; 57(4):443-51.BloodCervical epitheliumVaccination induces higher antibodiesVaccination induces higher antibodiesin the blood and site of infectionin the blood and site of infectionData show that v

11、accine-induced antibodies in the blood can reach to the site of infection1-3Higher antibody levels in the blood mean higher antibody levels at the site of infection4Antibodies neutralize the virus & prevent entry into cells5,6 Vaccination leads to strong and sustained neutralizing antibody which

12、 is markedly above the natural infection. Who is at Increased Risk of HPV InfectionWomen Remain at Risk for AcquiringHPV Infection Throughout Their Lifetimes Cumulative Risk of HPV Infection (%)Adapted from Muoz N et al. J Infect Dis. 2004;190:2077-2087. Reprinted with permission from The University

13、 of Chicago Press. Copyright 2004 by the Infectious Diseases Society of America. All rights reserved.Cohort of Colombian WomenN=1610Years01020304050012345Age at Baseline (Years)15-1920-2425-2930-4445+Increased Risk of HPV Infection in Young Females: Progression of the Transformation ZoneAdolescent f

14、emales have increased susceptibility to HPV infection, compared with adults.During and after puberty, the transformation zone is particularly vulnerable to infection and carcinogenesis.1,2 99% of HPV-related genital cancers arise within the transformation zone of the cervix.1After menopause, the cer

15、vix shrinks. As a result, the transformation zone may move into the endocervical canal.1.Castle PE. J Low Genit Tract Dis. 2004;8:224230. 2.2. ACOG Committee on Adolescent Health Care. Obstet Gynecol. 2004;104:891898. SCJ = squamocolumnar junction.Exposure to HPV at a Young Age Increases the Risk of

16、 Cervical Lesions and Cancer in Women1aMantle-Haenszel estimates adjusted for age only.1. La Vecchia C et al. Cancer. 1986;58:935941. Relative risks for CIN and invasive cancer increase with decreasing age of first sexual intercourse.Age at First Intercourse (Years)(n=206) (n=327) Reference Populati

17、on: First intercourse 23 years of age or neverAt the national level median age at sexual debut was 18 years in both rural and urban areas.National Behavioural Surveillance Survey (BSS) 2006, NACOMedian age (in years) sexual debut and genderOptimal Timing for Primary Prevention Is Before Exposure1“HP

18、V infection is sexually transmitted and is usually acquired within the first few years following sexual debut.”“Ideally, therefore, the vaccine should be administered before sexual debut, ie, before any risk of exposure to HPV.”World Health Organization 1. World Health Organization, United Nations P

19、opulation Fund. Preparing for the Introduction of HPV Vaccines: Policy and Programme Guidance for Countries. World Health Organization; 2006. SAGE = Strategic Advisory Committee of Experts; WHO = World Health Organization. 1. World Health Organization. Wkly Epidemiol Rec. 2009;84:116.Vaccination is

20、most effective when given to females nave to infectionPrimary target population is likely to be girls 9 or 10 through 13 years of ageWHO SAGE Recommendations: Primary Target Population for Vaccination1Timing Opportunity for Vaccination With Younger Adolescents1Decreasing incidence of office visits w

21、ith increasing age0.85 (0.76-0.95)0.83 (0.72-0.95)aAustria, Czech Republic, France, Germany, Greece, Hungary, Poland, Spain, Switzerland, the Netherlands, and the United Kingdom.CI = confidence interval.1. Berra S et al. Med Care. 2009;47:161167.N=7923Healthcare utilization in children and adolescen

22、ts 818 years of age in 11 European countriesa91011121314151617181920212223Age at Enrollment (Years)5007009001100130015001600Serum cLIA GMT With 95% CI, mMU/mLAdolescent FemalesYoung Adult FemalesSerum anti-HPV 6 responses 1 month after completion of vaccination regimen Per-protocol immunogenicity po

23、pulation (ages 926)aHigher Immune Response in Adolescents Versus Young Adults1aInclusive of protocols 007, 013, 015, 016 and 018; all GMTs measured using competitive Luminex immunoassay; women 2426 years of age were omitted in the figure because of small numbers. Similar results were observed for HP

24、V 11, 16, and 18. GMT = geometric mean titer.1. Giuliano AR et al. J Infect Dis. 2007;196:11531162. assessing efficacy of vaccineDifficulty in assessing efficacy of vaccine 1. Since most HPV infections resolve spontaneously how can vaccine efficacy be assessed2. Cervical cancer is a rare outcome of

25、a common oncogenic HPV infection.For every 1 million women infected with HPV100,000 will develop precancerous changes (CIN or cervical intraepithelial neoplasia)8,000 will develop carcinoma in situ (CIS)1,600 will develop invasive cervical cancer if precancerous changes and CIS are not detected or t

26、reated. So, just occurrence of HPV infection can not be used as an end point for evaluations of vaccine efficacy LARGE NUMBER OF SUBJECTS IN STUDY AND CONTROL GROUPDifficulty in assessing efficacy of vaccine criticism Preventing CIN 2/3 ,Not CaCxOutcomes for evaluation of HPV vaccinesSchematic repre

27、sentation of the natural history of cervical cancerdevelopment over time following genital HPV infectionsPagliusi SR et al.Vaccine 2004;23: 569578 VERY LONG DURATION STUDY primary objective of HPV vaccination is to reduce cervical cancer Due to ethical and time considerations need to use a surrogate

28、 end point in clinical trials of vaccine efficacy. The US Food and Drug Administration (FDA) examined the natural history of cervical cancer to define surrogate markers for cervical cancer. precancerous cervical lesions are used as cervical cancer surrogate CIN1 indicates active HPV infection and is

29、 not considered to be pre-cancerous CIN2 is treated in most women but is not an irrefutable cancer surrogate, as up to 40 percent of such lesions regress spontaneously CIN 3 cervical neoplasia has the lowest likelihood of regression and the strongest potential to become cancerous.acceptable surrogat

30、e . The US Food and Drug Administration considers grade 2 and 3 cervical lesions and AIS acceptable surrogate outcomes for cervical cancer, These lesions are the obligate precursor to invasive cervical cancerWHO Guidelines :endpoints (CIN 2/3) proxy for cervical cancer If HPV vaccination prevents th

31、e development of CIN 2/3 or AIS lesions this would constitute a demonstration that HPV vaccination prevents cervical cancer Two HPV vaccines availableIn India 2 HPV Types: HPV 16, 18 are for approximately 70% of all cervical cancer cases.100 HPV Types Have Been Identified115 HPV Types are OncogenicH

32、uman Papillomavirus (HPV)1.Munoz N et al. N Engl J Med 2003; 348(6):518-527 2.WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary Report 2010.+Aluminium salt(amorphous aluminium hydroxyphosphate sulphate AAHS)HPV

33、16 VLPsHPV 18 VLPsHPV 6 VLPsHPV 11 VLPsAntigensComposition of Bivalent and Quadrivalent vaccine +HPV 16 VLPsHPV 18 VLPsAntigensAS04 adjuvantAS04-containing vaccineAAHS-containing vaccineAdjuvant+Aluminium salt(Al(OH)3)MPL(monophosphoryl lipid AImmunostimulantBivalentQuadrivalent Efficacy of the vacc

34、ines Quadrivalent vaccine : Highly effective through 5 years post enrollment with no breakthroughs Bivalent vaccine : Highly effective through 8.4 years post enrollment with no breakthroughsImpact OF qHPV No breakthrough cases of HPV 16/18-related CIN2 or worse have been seen in the LTFU study up to

35、 8 years following vaccination with qHPV vaccine. Sufficient follow-up time has been accrued to definitively conclude the qHPV vaccine is effective up to 6 years following vaccination with a trend of continuing protection up to 8 years following vaccination.LONG-TERM EFFECTIVENESS OF GARDASIL IN THE

36、 NORDIC COUNTRIES. Kjaer et al. Poster presented at IPV 2012, Puerto Rico. Trends in HGAs (high-grade cervical abnormalities) in Women Aged 70% of all cervical cancer cases.100 HPV Types Have Been Identified115 HPV Types are OncogenicHuman Papillomavirus (HPV)1.Munoz N et al. N Engl J Med 2003; 348(

37、6):518-527 2.WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary Report 2010.+Aluminium salt(amorphous aluminium hydroxyphosphate sulphate AAHS)HPV 16 VLPsHPV 18 VLPsHPV 6 VLPsHPV 11 VLPsAntigensComposition of Biv

38、alent and Quadrivalent vaccine +HPV 16 VLPsHPV 18 VLPsAntigensAS04 adjuvantAS04-containing vaccineAAHS-containing vaccineAdjuvant+Aluminium salt(Al(OH)3)MPL(monophosphoryl lipid AImmunostimulantBivalentQuadrivalent Efficacy of the vaccines Quadrivalent vaccine : Highly effective through 5 years post

39、 enrollment with no breakthroughs Bivalent vaccine : Highly effective through 8.4 years post enrollment with no breakthroughsBivalent vaccine: Stronger and Longer Lasting antibody levels up to 8.4 years for both HPV 16 & 18Roteli-Martins CM, Naud P, Borba P, et al. Abstract presented at 28th ESP

40、ID congress, Nice, France, 2010. May 48.10,0001,00010010Serum cLIA GMT (mMU/ml)(log10 scale)6054363024181276320 1* *vaccinationGardasilNatural infectionAntibody levelseveral-fold higherthan naturalinfection10,0001,00010010Serum cLIA GMT (mMU/ml)(log10 scale)6054363024181276320 1Months* *vaccinationA

41、ntibody levelsimilar to naturalinfection levelsHPV 16HPV 18GardasilNatural infectionGardasil Phase II study up to 5 years Adapted from Olsson SE, et al. Vaccine 2007; 25:49314939; Villa LL, et al. Vaccine 2006; 24:55715583.Qudrivalent: Waning antibody levels against HPV 1835% seronegative by 5yrs fo

42、r HPV18Additional vaccine doseA fourth dose of 4 valent vaccine induces a booster response1Initial vaccinationAntibody level in the bloodTime1. Olsson SE et al. Vaccine 2007;25:49319Recall of immune memory byadditional dose of vaccine0510152025202425293034353940444549505455596064Age Group (Years)HPV

43、 infectionCervical Cancer HPV Prevalence (%)Cancer Incidence Rate (105)2520151050(n=3752)* Two different cohorts (cross-sectional study) followed during the same time span to measure the rate of high-risk HPV infection in one and the rate of cervical cancer in the other.1. Adapted from Bosch FX, Lor

44、incz A, Muoz N, Meijer CJLM, Shah KV. J Clin Pathol. 2002;55:244265, with permission from the BMJ Publishing Group. Peak of HPV infectionPeak of cervical cancer Age-Specific Rates of HPV Infection &Cancer Age for vaccination9 26 yearsLag Phase btw Infn & CA Cx 10- 20 yrsTimeHPV natural infec

45、tion(mucosal infection)HPV vaccinationHPV antibody level in the blood?Will natural HPV infection recall immune memory after antibodies have waned in vaccinated women? Injectable dose of HPV vaccine causes booster response suggesting recall memory Uncertain whether natural HPV infection will recall m

46、emory in vaccinated women strong correlation was observed between higher serum antibody titers and higher antibody titers in CVS(cervicovaginal secretions) for both HPV-16 and HPV-18 =protection Assessment of Efficacy ? On what parameter the efficacy of HPV vaccine should be evaluated?A. Antibody ti

47、tersB. Clinical Efficacy against CIN2/3 or AISCIN Cervical Intraepithelial Neoplasia, AIS Adenocarcinomain situ Minimum protective levels of Ab are not defined due to lack of breakthrough infections in subjects who received the vaccine. Role of cellular immunity ?Optimal Timing for Primary Preventio

48、n Is Before Exposure1“HPV infection is sexually transmitted and is usually acquired within the first few years following sexual debut.”“Ideally, therefore, the vaccine should be administered before sexual debut, ie, before any risk of exposure to HPV.”World Health Organization 1. World Health Organi

49、zation, United Nations Population Fund. Preparing for the Introduction of HPV Vaccines: Policy and Programme Guidance for Countries. World Health Organization; 2006. Timing Opportunity for Vaccination With Younger Adolescents1Decreasing incidence of office visits with increasing age0.85 (0.76-0.95)0

50、.83 (0.72-0.95)aAustria, Czech Republic, France, Germany, Greece, Hungary, Poland, Spain, Switzerland, the Netherlands, and the United Kingdom.CI = confidence interval.1. Berra S et al. Med Care. 2009;47:161167.N=7923Healthcare utilization in children and adolescents 818 years of age in 11 European

51、countriesaSAGE = Strategic Advisory Committee of Experts; WHO = World Health Organization. 1. World Health Organization. Wkly Epidemiol Rec. 2009;84:116.Vaccination is most effective when given to females nave to infection with vaccine-related HPV types Primary target population is likely to be girl

52、s 9 or 10 through 13 years of ageWHO SAGE Recommendations: Primary Target Population for Vaccination1407324239595544PCV113116733461272a573281029512630535666RhPV1701845583352163531Papillomavirus phylogenetic treeHPV 16 is most closely related to HPV 31HPV 18 is most closely related to HPV 45 Adapted

53、from de Villiers E, et al. Virology 2004; 324:1727.In India, HPV 16, 18, 31 & 45 account for90% Squamous Cell Carcinoma95% Cervical AdenocarcinomaWHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary Report 2010

54、.HPV Types% Efficacy(95% CI)HPV 16/18*198.2% *(93.5-99.8) *HPV 31*270% *(32.1-88.2) *HPV 45*2-51.9% *(-1717.8-82.6) *10 non-vaccine oncogenic HPV Types*232.5% *(6-51.9) *Per-Protocol Efficacy (PPE) population (n= all 3 vaccinations within 1 year of enrolment, no major protocol deviations and nave to

55、 the relevant HPV type(s) prior to dose 1 and through 1 month Postdose 3 (Month 7).* The efficacy population that was negative for 14 HPV types (prespecified analyses), n=9296.*The efficacy for HPV 16/18 related CIN 2/3 or AIS is based on data from protocols 005 (16-related endpoints only), 007, 013

56、, and 015, Median follow-up of 3.6 years (n=16957).* Combined Phase III efficacy database after a median follow-up of 3.7 years (n=9296). References:1.Gardasil SPC. http:/www.emea.europa.eu/humandocs/PDFs/EPAR/gardasil/H-703-PI-en.pdf (Accessed on 4th August 2009)2.Brown DR et al. The Impact of Quad

57、rivalent Human Papillomavirus (HPV; Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine on Infection and Disease Due to Oncogenic Nonvaccine HPV Types in Generally HPV-Naive Women Aged 1626 Years. JID 2009; 199: 926-35.4 VALENT efficacy: Summary 3.7 Yr4 VALENT efficacy: Summary 3.7 YrCross Prote

58、ction Against HPV Types 45 & 31 Incident Infection 6.4 yrs ATP analysisn = number of subjects reporting at least one event in each group Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008 Should we use the HPV vaccine ?GLOBOCAN 2002 Cancer Incidence, Mortality andPrevalence India Cervi

59、cal cancer ranks No. 1 among cancers in Indian women followed by breast cancer Every year 132000 Indian women are diagnosed with Cervical cancer and around 74000 die from the disease 1 out of 4 women who die due to Cervical Cancer in the world is an Indian Indian women face a 2.5% cumulative lifetim

60、e risk of cervical cancer and 1.4% cumulative risk of death from cervical cancer. Disease burden Effective vaccine Safe vaccine Cost Availability of other interventionscreening programmesscreening programmes Invasive cancer incidence and mortality has fallen by 50% -80% in developed world The highest burden of disease (u