HPV vaccines. Margaret Stanley Department of Pathology Cambridge

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1 HPV vaccines Margaret Stanley Department of Pathology Cambridge 1

2 Disclosure Statement Dr. Margaret Stanley has acted as a consultant and advisor for Merck Sharp & Dohme, GlaxoSmithKline, and Sanofi Pasteur Merck Sharp & Dohme. 2

3 What are human papillomaviruses? What diseases do they cause? Prophylactic HPV vaccines Formulation, mechanism of action Implementation, effectiveness Where next? 3

4 What are human papillomaviruses? What diseases do they cause? Prophylactic HPV vaccines Formulation, mechanism of action Implementation, effectiveness Where next? 4

5 HPV Non enveloped dsdna virus, simple capsid of 2 proteins L1 and L2 Common virus with >170 types identified Infects cutaneous and mucosal squamous epithelia Exclusively intra epithelial life cycle infect the mucosal epithelia of women and men 2 groups low risk types causing warts HPV 6,11 13 high risk types causing cancer 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,68 HPV 16,18 most important 5

6 Estimated annual new HPV-related disease cases among Males and Females Globally 5% of all cancers estimated to be caused by HPV Penile cancer 10,500 Male Female Vulvar & vaginal cancer Anal cancer Anal cancer Head and neck cancer Head and neck cancer Cervical cancer Genital warts 17,300,000 14,700,000 Genital warts 6

7 Worldwide HPV-Related Disease Burden: Penile cancer 1 11,000 Male Female 21,000 Vulvar & vaginal cancer 1 Oropharyngeal cancer 1 17,000 4,400 Oropharyngeal cancer 1 Anal cancer 1 11,000 13,000 Anal cancer 1 530,000 Cervical cancer 1 x 60 fold 9,000,000 High-grade cervical dysplasia 2,3, * 21,900,000 Low-grade cervical dysplasia 2,3, Genital warts 4,5, Genital warts 4,5, 17,300,000 14,700,000 *Estimated 90% of high-grade cervical lesions are HPV related 3 ; Estimated 73% of low-grade cervical lesions are HPV related 3 ; Estimated gender ratio of genital warts: 54% males; 46% females 6 1. Forman D, et al. Vaccine. 2012;30:F12-F23; 2. World Health Organization; 3. Guan P, et al. Int J Cancer. 2012;131: ; 4. World Health Organization; 5. Greer CE, et al. J Clin Microbiol. 1995;33: ; 6. Public Health England. 7

8 Annual new cancers and genital warts cases related to HPV in Males and Females in Europe Penile Cancer ,700 Vulvar & Vaginal Cancer Anal Cancer 1,600 2,800 Anal Cancer H&N Cancer 11,600 2,300 H&N Cancer 23,000 Cervical Cancer MALE Genital warts 329, ,000 FEMALE Genital warts Annual number of new cancer cases calculated based on crude incidence rates from IARC database ( ) and population estimate Eurostat 2008; estimate Globocan 2008 for cervical cancer 8

9 % among HPV positive cases RELATIVE CONTRIBUTION of HPV 16,18,45,31,33,52,58,35 & 6 100% CERVIX VULVA VAGINA PENIS ANUS OROPHARYNX 80% 60% 40% 20% 0% HPV16 HPV18 HPV45 HPV31 HPV33 HPV52 HPV58 HPV35 HPV6 The 8 most common HPV types in CaCx 9 De Sanjose et al 2010 Lancet Oncol. 2010;11: Serrano B, 2012 Infect Ag Cancer;7:38. de Sanjose S, 2013 Eur J Cancer;49:3450 Alemany L 2015 Int J Cancer;136:98 Castellsague X 2016 JNCI;108 Alemany L 2016 Eur J Urol Jan.

10 What are human papillomaviruses? What diseases do they cause? Prophylactic HPV vaccines Formulation, mechanism of action Implementation, effectiveness Where next? 10

11 Prophylactic HPV VLP Vaccine Profiles Cervarix Bivalent vaccine Gardasil Quadrivalent vaccine Gardasil9 Nonavalent vaccine Manufacturer Glaxo Smith Kline Merck Merck Volume Per dose 0.5ml Per dose 0.5ml Per dose 0.5ml Adjuvant ASO4: Al(OH) 3 MPL 500mg 50mg Amorphous Aluminium Hydroxyphosphate sulphate 225mg Amorphous Aluminium 500mg Hydroxyphosphate sulphate Antigens L1 HPV16 20µg L1 HPV18 20µg L1 HPV6 20µg L1 HPV11 40µg L1 HPV16 40µg L1 HPV18 20µg L1 HPV6 30µg L1 HPV11 40µg L1 HPV16 60µg L1 HPV18 40µg L1 HPV31 20µg L1 HPV33 20µg L1 HPV45 20µg L1 HPV52 20µg L1 HPV58 20µg Expression system Hi-5 Baculovirus Yeast: Saccharomyces cereviseae Yeast Saccharomyces cereviseae Schedule Intra muscular 0, 1, 6 months Intra muscular 0,2,6 months Intra muscular 0,2,6 months FDA licensed EMA licensed

12 Prophylactic HPV vaccines consist of Virus-Like Particles (VLPs) L1 Expressed in yeast or baculovirus 5 L1 proteins 1 L1 pentamer Pentamers self-assemble Noninfectious HPV Virus Like Particles (VLP) 12 Gardasil SmPC. EMEA, Kirnbauer R, Booy F, Cheng N, et al. Proc Natl Acad Sci USA. 1992;89: Modis Y, Trus BL, Harrison SC. The EMBO Journal. 2002;21: Stanley M, Lowy DR, Frazer I. Vaccine 2006; 24 suppl 3 : S106-13

13 mechanism of protection of HPV VLP vaccines Assumption mechanism of protection is neutralising antibody mediated Evidence passive transfer of purified IgG from hyperimmune donors immunised with L1 VLPs completely protects naive recipients from viral challenge Breitburd et al J Virol 1996 Suzich et al

14 Antibody responses to HPV in natural infection and after vaccination Natural infection 70-80% women 20-30% men seroconvert Antibody response to HPV infection is typically slow and weak Neutralising antibody responses are to L1 Cross neutralising antibodies not detected Antibody generated in natural infections in women is partially protective against subsequent incident infection but not in men Avidity index very variable HPV L1 VLP vaccination In clinical trials 100% women and men sero-convert Peak antibody titres are x greater than in natural infections Neutralising antibody persists for >9 years post immunisation Both type specific and cross neutralising antibodies detected No breakthrough disease caused by vaccine HPV types detected after 10 years follow up in RCTs Avidity index consistently high No antibody threshold level for the protection provided by HPV vaccines has been identified No immune correlate 14

15 VLPs are very immunogenic Size Enter lymphatics and blood vessels easy access to lymph nodes 50nm Geometry Regular repeat pentamer structure across the particle activate B cells and antigen presenting cells induce robust antibody even in the absence of adjuvant (cross link B cell receptors, activate TLRs) Evoke robust memory responses Serological memory persistence of antibody 15 Reactive memory anamnestic or recall response

16 Epithelial microabrasion and wound healing are necessary for HPV infection cervix vagina vulva penile shaft peri-anal skin Microtrauma to the epithelium exposes the basement membrane to which HPV binds before entering the wound keratinocyte 1,2 Microwounding will result in serous exudation rapid access of serum IgGs to the virus particles 1 Roberts J etal Nature Med 13:857, Kines etal 2009 PNAS 106,

17 What are human papillomaviruses? What diseases do they cause? Prophylactic HPV vaccines Formulation, mechanism of action Implementation, effectiveness Where next? 17

18 Vaccines depend for their impact at the population level by reducing transmission Genital HPV infection is usually but not always sexually transmitted Infection occurs early after the onset of sexual activity Immune responses to the vaccines are optimal in 9-13 year olds Routine vaccine cohorts 9-15 year olds 18

19 Prophylactic HPV VLP Vaccine Profiles Cervarix Bivalent vaccine Gardasil Quadrivalent vaccine Gardasil9 Nonavalent vaccine Manufacturer Glaxo Smith Kline Merck Merck Volume Per dose 0.5ml Per dose 0.5ml Per dose 0.5ml Adjuvant ASO4: Al(OH) 3 MPL 500mg 50mg Amorphous Aluminium Hydroxyphosphate sulphate 225mg Amorphous Aluminium 500mg Hydroxyphosphate sulphate Antigens L1 HPV16 20µg L1 HPV18 20µg L1 HPV6 20µg L1 HPV11 40µg L1 HPV16 40µg L1 HPV18 20µg L1 HPV6 30µg L1 HPV11 40µg L1 HPV16 60µg L1 HPV18 40µg L1 HPV31 20µg L1 HPV33 20µg L1 HPV45 20µg L1 HPV52 20µg L1 HPV58 20µg Expression system Hi-5 Baculovirus Yeast: Saccharomyces cereviseae Yeast Saccharomyces cereviseae Schedule >15 years <15years Intra muscular 0, 1, 6 months 0,6 months Intra muscular 0,2,6 months 0,6 months Intra muscular 0,2,6 months FDA licensed EMA licensed

20 Countries With HPV Vaccine in the National Immunization Program 1 Introduced a to date (63 countries or 32.5%) Not available, not introduced/no plans (131 countries or 67.5%) Not applicable a Includes partial introduction. 1. Vaccine in National Immunization Programme Update. Map production Immunization Vaccines and Biologicals (IVB), WHO/IVB Database, World Health Organization website. Accessed July 28,

21 First systematic review on impact following HPV vaccination PERIOD: NUMBER OF STUDIES: 20 (140M p-y of follow up) Compare outcomes in post- vs pre-vaccination periods Drolet et al, Lancet infect Dis

22 RR of GW during the first 4 years after Gardasil introduction relative to pre-vaccination period GIRLS & WOMEN COVERAGE >50% GIRLS & WOMEN COVERAGE <50% Drolet et al, Lancet Infect Dis

23 Australia: Near disappearance of genital warts after commencement of national HPV program National HPV vaccination programme 1. Read et.al., Sex Transm Infect 2011; 87:544e547. doi: /sextrans Almost 90% decline in new cases of genital warts in both men and women < 21 yrs old 23

24 Figure 2. Crude HPV genotype prevalence in women aged 21 years and younger, stratified by Australian-born Eric P F Chow et al., Vaccine 15,(11), 2015, Human papillomavirus in young women with Chlamydia trachomatis infection 7 years after the Australian human papillomavirus vaccination programme: a cross-sectional study 24

25 HPV 16/18 Prevalence (%) HPV 16/18 Prevalence By Age: Pre-vs. Post-immunisation Amongst Those Testing HR HPV Positive (England) Estimated vaccination coverage 60 65% 30% 0% Age group years years years Pre-immunisation Post-immunisation Data from Mesher etal 2013 Vaccine 17:

26 Australia: State of Victoria data linkage study HPV vaccine effectiveness for CIN outcome to end 2011 by age of vaccination in 2007 % Disease Reduction 2011 Age of vaccination in 2007 Gertig et al 2013 BMC Med 11:

27 What are human papillomaviruses? What diseases do they cause? Prophylactic HPV vaccines Formulation, mechanism of action Implementation, effectiveness Where next? gender neutral vaccination?1 dose 27

28 Why not immunise boys Pros Burden of disease in men The prevalence of genital HPV infection varies with age in women but not in men Fewer men (20-30%) than women (70-90%) make an immune response to HPV infection Men are not protected by antibody made after natural infection constantly reinfected BUT HPV vaccines protect against HPV infection and disease in men 28

29 Genital HPV: age related prevalence Women Men Manchester UK Peto et al Brit J Cancer 2004 Brazil, Mexico USA Giuliano AR et al. Cancer Epidemiol Biomarkers Prev. 2008;17:

30 Low Serum Antibody Response to HPV Infection in Men HPV-16 seroconversion values for males 1 were lower than previously reported values for females 2 Prevalent infections: 20% males 1 vs 94% females 2 Incident infections: 7% males 1 vs 67% females 2 HPV type (n) Seroconversion (%) at 24 mo (95% CI) Combined analysis (prevalent and incident infection) Prevalent infection a Incident infection a 16 (97) 13 ( ) (35) 36 ( ) (25) 8 ( ) (8) 12.5 ( ) (25) 4 ( ) (15) 6.7 (1 38.7) (36) 21.1 ( ) a Values from Kaplan-Meier estimates for cumulative type-specific seroconversion after prevalent or incident infections. CI=confidence interval; mo=months. 1. Edelstein ZR et al. J Infect Dis. 2011;204: Carter JJ et al. J Infect Dis. 1996;174:

31 Prophylactic Efficacy of Gardasil Against HPV 6/11/16/18 High Grade Anal Disease and EGL GARDASIL n=194 Placebo n=208 % # Cases IR/100 PY # Cases IR/100 PY Efficacy 95% CI AIN ,95 AIN ns AIN ns MSM Per Protocol Efficacy Population, End of Study data, P020 Palefsky J etal., N Egl J Med 365:1576 GARDASIL n = 1,397 Placebo n = 1,408 % # Cases IR/100 PY # Cases IR/100 PY Efficacy 95% CI EGL , 98 Per Protocol Efficacy Population, End of Study data, P020 Giuliano AR et al N Engl J Med, :

32 Cons Why not immunise boys MSW get herd protection from female only vaccination when coverage >80% - not cost effective MSM not protected by female only vaccination but could be vaccinated as a high risk group 32

33 Herd protection is not herd immunity Herd protection for men depends upon high HPV vaccine coverage in women Sustainability of herd protection depends upon sustained high coverage in women Immunising before onset of sexual activity protects ALL men irrespective of sexual preference Reduction in virus circulating in the population is essential for maximum disease impact, achieved by immunising boys and girls true herd immunity 33

34 Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA trials Aimée R Kreimer*, Frank Struyf*, Maria Rowena Del Rosario-Raymundo, Allan Hildesheim, S Rachel Skinner, Sholom Wacholder, Suzanne M Garland, Rolando Herrero, Marie-Pierre David, Cosette M Wheeler, for the Costa Rica Vaccine Trial and the PATRICIA study groups Lancet Oncology June We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort ( received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77 0% (95% CI ), two doses was 76 0% ( ), and one dose was 85 7% ( ). 34

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36 A and B, HPV16 (top) and HPV18 (bottom) specific antibody geometric means: by number of vaccine doses and study visit by American Association for Cancer Research Safaeian M et al. Cancer Prev Res 2013;6:

37 Human papilloma virus: key facts for prophylactic vaccination Absolutely restricted host range humans only no animal reservoir Mucosal oncogenic HPVs sexually transmitted Transmission requires intimate contact Vaccine HPV type infection and disease prevented by HPV VLP vaccines No evidence for HPV type replacement in vaccinated cohorts after 10 years - genetically stable virus Eradication of vaccine HPVs? 37

38 Thank you 38