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Hpv vaccine update
- 1. D R .S U K H W I N D E R S I N G H HPV VACCINES: AN UPDATE
- 2. OUTLINE • Global burdenof HPV related cancers • Human papilloma virus • HPV life cycle in cervix • Types of HPV • Association between Human Papillomavirus and Malignant Diseases • Clinical manifestations • HPV disease prevention • History of HPV vaccine • Vaccine profile • Mechanism of action HPV vaccines • Natural history of HPV infection & carcinoma cervix • Whome to vaccinate • Possible HPV vaccination target groups and special populations • Vaccination recommendations for HPV • Adverse effect of HPV vaccine • HPV vaccine delivery strategy • Progress in HPV vaccine implementation • Hpv vaccination in India • Other way to prevent cervical cancer • Therapeutic HPV vaccines
- 3. GLOBAL BURDEN OFHPV RELATED CANCERS Cervical cancer • 2,784 million women aged 15 years and older worldwide are at risk of developing cervical cancer • 4th most common cancer among women in the World • 2nd most common cancer among women aged 15-44 years Worldwide
- 4. CERVICAL CANCER New annual cervicalcases • India – 122,844 • World – 527,624 Annual deaths due to cervical cancer • India –67,477 • World – 265,672 23% 77% India World 27% 73% India World
- 5. ANOGENITAL CANCERS OTHERTHAN THE CERVIX • Anal cancer: • average worldwide incidence of 1 per 100,000 • 27,000 new cases every year • Vulvar cancer: • 4% of all gynaecologic cancers • Vaginal cancer: • 2% of all gynaecologic cancers • Penile cancer: • 22,000 new cases every year de Martel C et al. Lancet Oncol 2012;13(6):607-15
- 6. HUMAN PAPILLOMA VIRUS •Papillomavirus genus • Papillomaviridae family • Non-enveloped virus • 55 nm in diameter • Icosahedral capsid composed of 72 capsomeres enclosing a ds circular DNA genome
- 7. HUMAN PAPILLOMA VIRUS •genome - 7900 base pairs • the genome encodes several early genes (E1, E2, E4, E5, E6, and E7) • structural late genes (L1 and L2) • 200 HPV types known
- 8. GENE CATEGORY GENE FUNCTION Early genes E1Viral DNA replication E2 • viral transcription • DNA replication • segregation of viral genomes E4 • HPV genome amplification • virus maturation • release of virions E5 • se activity of E6 and E7 • Generate aneuploidy and chromosomal instability E6 • Bind and degrade the tumor-suppressor protein p53 • inhibit apoptosis E7 Bind and degrade the tumor-suppressor protein pRB Late genes L1 • Major capsid protein • attachment to cell surface receptors • highly immunogenic & induce the production of neutralizing type-specific antibodies against the virus L2 • Minor capsid protein • helps packaging of viral DNA into capsids
- 9. HPV LIFE CYCLEIN CERVIX
- 11. • Non-oncogenic HPV: •6,11,32,40,42,43,44,54,55,57,61,62,64,71,72,74,81,84,87,89, 90,91 • Oncogenic HPV types: • High risk oncogenic virus • 16,18,31,33,35,39,45,51,52,56,58,59 • Probable/possible carcinogen • 26,30,34,53,66,67,68,69,70,73,82,85,97 TYPES OF HPV
- 12. ASSOCIATION BETWEEN HUMAN PAPILLOMAVIRUSAND MALIGNANT DISEASES Worldwide India Human Papillomavirus and Related Diseases Report April 2017
- 13. ASSOCIATION BETWEEN HUMAN PAPILLOMAVIRUSAND MALIGNANT DISEASES Forman D et al. Vaccine 30s 2012 Lacey CJ et al 2006
- 14. CLINICAL MANIFESTATIONS • Cutaneouswarts • deep plantar warts • common warts • plane or flat warts • Epidermodysplasia Verruciformis • Anogenital Warts • Recurrent Respiratory Papillomatosis • Cancers • Cervical • Anal • Vaginal • Vulvar • Penile • Oro-pharyngeal cancer
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- 17. THE NEED FORVACCINATION AGAINST CERVICAL CANCER • Natural HPV infection induces a weak immune response • Vaccination induces higher antibodies in blood and site of infection which neutralizes virus.
- 18. WHY VACCINATION ISTHE BEST FORM OF PREVENTION • All genital HPV infections can’t be prevented except by abstinence and lifetime mutual monogamy • Barrier methods of contraception confer a protection against HPV infection – still questionable • Asymptomatic infection except for genital warts • In developing country like India, large-scale routine screening is difficult to achieve.
- 19. HISTORY OF HPVVACCINE • 1977 - Dr.Harald zur Hausen detected HPV in warts and cervical cancer • 2006 – US FDA approved Gardasil vaccine • 2008 - Dr. Hausen received Nobel Prize for his work on HPV • 2009 - FDA approved Cervarix vaccine • 2014 - FDA approved 9-valent HPV vaccine • 2016 - U.S. FDA approved adding a 2-dose schedule for 9-valent HPV vaccine (Gardasil 9) for adolescents ages 9 -14 years
- 20. VACCINE PROFILE • 2licensed prophylactic HPV vaccines • Bivalent (16,18) • Quadrivalent (6,11,16,18) • Both produced by recombinant technology
- 21. VACCINE PROFILE • Virus-likeparticles (VLP) • Purified L1 protein • form empty shells • do not contain viral genetic material or live biological product • non infectious.
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- 24. MECHANISM OF ACTIONHPV VACCINES Bind to viral particles Transudate from capillaries to basal stem cells in the genital epithelial mucosa L1- Neutralizing serum IgG 1–4logs > natural infection Anti-L2 antibodies cross-neutralizing VLP(L1 & L2)-based HPV vaccination
- 25. NATURAL HISTORY OFHPV INFECTION & CARCINOMA CERVIX • In natural infection, antibodies against L1 appear 6–8 months following infection • In 50–70% of infected individuals • Other viral proteins (E1, E2 and E6) do not elicit antibody responses • IgM response occurs first and decays early • IgG response appears late
- 26. CROSS-TYPE PROTECTION • Gardasil– HPV 31 • Cervarix - HPVs 31,33,52,45 and 51
- 27. WHOME TO VACCINATE •Girls aged 9 to 14 years prior becoming sexually active • Catch-up vaccination till 45 year old females • Males
- 28. EVALUATION BEFORE VACCINATION •Contraindicated : • Known hypersensitivity to any vaccine components • Serious bleeding disorders • Pregnancy • Delay vaccination - severe febrile illness • HPV serologic or DNA testing or cervical cytology are not recommended before vaccination
- 29. POSSIBLE HPV VACCINATIONTARGET GROUPS AND SPECIAL POPULATIONS Primary target group of females: • Girls 9–14 years of age • HPV vaccines are most efficacious- • before onset of sexual activity • females naive to vaccine-related types • Primary vaccine target group depend on • country’s vaccine licensing indications • age of initiation of sexual activity of females
- 30. POSSIBLE HPV VACCINATIONTARGET GROUPS AND SPECIAL POPULATIONS Secondary or “catch-up” populations of females: • females 15 years and older • May decrease impact of vaccination on cervical cancer- shorter interval between vaccination and sexual exposure to vaccine related HPV types
- 31. SPECIAL POPULATIONS Pregnant andlactating females: • HPV vaccination not recommended in pregnant females • If pregnant women vaccinated, vaccination be discontinued until completion of the pregnancy
- 32. SPECIAL POPULATIONS Immunocompromised individuals: •Limited Data • HPV vaccination of target group before onset of sexual activity reduces risk of administering HPV vaccines to HIV-infected individuals • Countries with HPV vaccines in national immunization programmes do not vaccinate females whose HIV status is unknown
- 33. ACIP-RECOMMENDATIONS FOR HPV •On 19 October 2016, CDC and ACIP recommended : Females < 15 years should receive 2 doses of HPV vaccine at least 6 months apart rather than the previously recommended 3 doses.
- 34. ACIP-RECOMMENDATIONS FOR HPV 4vHPV& 2vHPV vaccine: • <15 years (Target group) – 2 doses (0, 6-12 months) • If interval between doses is <5 months - 3rd dose given at least 6 months after the 1st dose • 16-26 years (Catch-up group): • 3 doses ( 0, 2, 6 month) • Interval between 1st & 2nd dose - 6–12 weeks • Interval between the 2nd & 3rd dose - 12–23 weeks • >26 years- geometric mean titres lower than 16-26 years • Concomitant Administration with Other Vaccines: • meningococcal conjugate vaccine, tetanus, diphtheria, and acellular pertussis vaccine; inactivated polio vaccine and hepatitis B vaccine • No effect on seroconversion rates and geometric mean titres • Pregnancy - Category B
- 35. ACIP-RECOMMENDATIONS FOR HPV 4vHPV& 2vHPV vaccine: • Interchangeability of HPV Vaccine Products • Vaccination completed with same HPV vaccine product • if providers don’t have same HPV vaccine product either HPV vaccine product may be used to continue or complete the series for females to provide protection against HPV 16 & 18. • Only 4vHPV used in males.
- 36. ADMINISTRATION • HPV vaccineshaken well before administration • Dose of vaccine - 0.5 ml • Intramuscularly, preferably deltoid muscle or antero- lateral thigh
- 37. INTERRUPTED SCHEDULE (0,2,6M) •Interrupted after 1st dose: • 2nd dose to be given as soon as possible and 2nd & 3rd dose be separated by at least 12 weeks • Interrupted after 2nd dose: • 3rd dose to be given as soon as possible
- 38. INCORRECTLY VACCINATED (0,2,6M) •Average interval between : • 1st & 2nd dose - 6–12 weeks • 2nd & 3rd dose - 12–23 weeks • Minimum interval: • 1st & 2nd dose - 4 weeks • 2nd & 3rd dose - 12weeks Inadequate doses and shorter intervals – vaccines schedule readministered
- 39. SPECIAL SITUATIONS Abnormal PapTest, Known HPV Infection, Anogenital Warts, or HPV-Associated Lesions: • Protection against vaccine HPV types only • Might not be infected by any of the vaccine HPV type • Vaccination also recommended for: females regardless of abnormal Pap test result Females/males regardless of known HPV infection, HPV-associated precancer lesions, or anogenital warts Females with abnormal cervical cancer screening
- 40. SPECIAL SITUATIONS Immuno-compromised Persons: • Vaccine efficacy between immuno-compromised and immuno- competent persons – unclear • ACIP recommends same vaccination schedule for immuno- compromised Men Who Have Sex with Men: • Higher risk of HPV infection • ACIP recommends routine vaccination with 4vHPV
- 41. SPECIAL SITUATIONS Lactating Women: •Can receive HPV vaccine History of Sexual Abuse or Assault: • Risk of HPV infection • ACIP recommends HPV vaccination beginning at age 9 years with 2-dose series • Older females & males victims should receive HPV vaccine through the recommended ages
- 42. HPV VACCINES SHOULD NOTBE GIVEN TO… • History of allergies to any vaccine component • 4vHPV & 9vHPV - hypersensitivity to yeast (Saccharomyces cerevisiae) • 2vHPV - anaphylaxis caused by latex • Moderate or severe acute illnesses • Pregnant women
- 43. DURATION OF VACCINEPROTECTION • HPV vaccines offer long-lasting protection • Studies followed vaccinated individuals for around ten years - no evidence of protection decreasing over time
- 44. ADVERSE EFFECT OFHPV VACCINE Common HPV vaccine reactions which resolve spontaneously and rarely require treatment are: • Redness, pain, swelling, or induration at injection site • Fever • Headache, myalgia, arthralgia • Nausea, vomiting, diarrhea, abdominal pain • Pruritis, rash, urticaria • Syncope, dizziness
- 45. SHOULD BOYS BEVACCINATED?? • Benefits: • protection against HPV-associated diseases in men • enhanced herd immunity with consequent reduction in HPV transmission in populations • Can countries attain sufficiently high male vaccination coverage rates?----Most promising question
- 46. HPV VACCINE DELIVERYSTRATEGY Ideal HPV vaccine delivery strategy outlined by WHO in 2013: • compatible with existing vaccine-delivery infrastructure and cold chain capacity • affordable, cost-effective and sustainable • able to achieve the highest possible coverage HPV vaccine delivery strategies: • Vaccine delivery at health-care facilities • Vaccine delivery through outreach: • School-based outreach • Other outreach • Vaccine delivery through campaigns
- 47. PROGRESS OF HPVVACCINE IMPLEMENTATION • January 2008, 13 countries had recommended catch-up vaccination of older adolescent females or young women • 2009 – 1st WHO paper on HPV vaccines published • Both 4vHPV & 2vHPV vaccine licensed in > 100 countries • July 2009 – HPV vaccines were WHO pre-qualified • May 2011 – 32 countries worldwide introduced HPV vaccine in their national immunization program • 2015 – 65 countries worldwide introduced HPV vaccine in their national immunization program
- 48. HPV VACCINE- INDIA •HPV vaccines introduced under pilot projects in 2006 • GAVI states- a coverage of 25-70% over 10 years in a country like India can save > 1 million lives. • Pap testing & HPV DNA testing or HPV antibody before vaccination is not needed • Prevention of cervical cancer continues to be largely neglected in India
- 49. AVAILABILITY OF VACCINEIN INDIA • GlaxoSmithKline and Merck & Corp sell in India • No manufacturing facility in India • No Indian company selling HPV vaccines • But some Indian companies have HPV vaccines in their pipeline • Cervarix and Gardasil have India import license of validity up to December 2016 and June 2018 respectively.
- 50. COST OF HPVVACCINE-INDIA
- 51. HPV VACCINATION ININDIA Indian Academy of Pediatrics Committee on Immunisation (IAPCOI) recommends offering HPV vaccine to all females who can afford the vaccine. • Schedule same as given by ACIP
- 52. HPV VACCINATION ININDIA
- 53. HPV VACCINE-RESEARCH • Researchcarried out in India: • Capsomere vaccines – • more cheap • manufactured in E.coli • require no cold-chain. • Monovalent vaccines (based on the L2 protein)- • Broader protection • Needle free delivery systems
- 54. PIPELINE VACCINES Market assesmentof newer vaccines, 2015
- 55. OTHER WAYS TOPREVENT CERVICAL CANCER • Reduce high-risk sexual behaviours • Condom use • Avoid or reduce tobacco use and smoking • Seek prompt treatment of sexually transmitted infections
- 56. THERAPEUTIC HPV VACCINE???? •Several types developed and tested in preclinical and clinical trial • Types : • live vector • protein or peptide • nucleic acid • cell-based vaccines • Whole cell based type • Tumour cell based type • Majority target HPV onco-proteins E6 and E7
- 57. THERAPEUTIC HPV VACCINES RECENTLYUSED IN CLINICAL TRIALS TYPE VACCINE ANTIGEN CONSTRUCT Bacterial Vector Based Lm-LLo-E7 (ADXS11-001; ADXS-HPV) HPV-16 E7 prfA- defective Listeria monocytogenes strain GLBL101c HPV16-E7 expressing modified version of HPV16-E7 Recombinant Lactobacillus casei Viral Vector Based TA-HPV HPV-16/18 E6/E7 Recombinant Vaccinia virus TG4001 HPV-16 E6/E7 Recombinant modified Vaccinia Ankara- expressing HPV-16 E6, E7, and IL-2 MVA E2 HPV-16 E2 Recombinant Modified Vaccinia Ankara virus
- 58. THERAPEUTIC HPV VACCINES RECENTLYUSED IN CLINICAL TRIALS TYPE VACCINE ANTIGEN CONSTRUCT Peptide/Protein Based HPV16-SLP HPV-16 Combination of nine HPV-16 E6 and four HPV-16 E7 E6/E7 synthetic peptides with incomplete Freund’s adjuvant GL-0810 HPV-16 antigen HPV-16 immunomodulatory peptide with adjuvant Montanide and GM-CSF Pepcan + Candin HPV-16 E6 HPV16 E6 peptides combined with Candida skin testing reagent candin GTL001 (ProCervix) HPV-16 and HPV-18 Recombinant HPV16 and HPV18 E7 proteins fused to catalytically inactive Bordetella pertussis CyaA expressed in E. coli
- 59. THERAPEUTIC HPV VACCINES RECENTLYUSED IN CLINICAL TRIALS TYPE VACCINE ANTIGEN CONSTRUCT Peptide/Protein Based TA-CIN HPV-16 E6/E7/L2 HPV16 E6E7L2 fusion protein TA-CIN + TA HPV HPV-16/18 E6/ E7/L2 HPV16 E6E7L2 fusion protein and vaccinia virus with HPV16/18 E6/E7 Nucleotide Based pNGVL4a-sig/ E7(detox)/ HSP70 + TAHPV HPV-16/18 E6/E7 Plasmid encoding mutated form of HPV16-E7 linked to sig and HSP70 and vaccinia virus with HPV16/18 E6/E7 pNGVL4a-CRT/ E7(detox) HPV-16 E7 Plasmid encoding mutated form of HPV16-E7 linked to CRT GX-188E HPV-16/18 E6/E7 Plasmid encoding fusion protein of HPV 16/18 E6/E7 linked to Flt3L and tpa VGX-3100 HPV-16/18 E6/E7 Mixture of two plasmids encoding optimized consensus of E6 and E7 antigen of HPV 16 and 18
- 60. THERAPEUTIC HPV VACCINES RECENTLYUSED IN CLINICAL TRIALS TYPE VACCINE ANTIGEN CONSTRUCT Whole Cell Based DC + KLH HPV-16 and HPV-18 E7 Dendritic Cells pulsed with HPV-16 and HPV-18 E7 and keyhole limpet hemocyanin DC HPV antigens DC pulsed with HPV+ tumor lysate
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Editor's Notes
- #5 India has a population of 432.2 million women aged 15 years and older who are at risk of developing cancer.5 It is the second most common cancer in women aged 15–44 years
- #8 More than 184 are recognized
- #17 Three different types of tests are currently available: — Conventional (Pap) and liquid based cytology (LBC) — Visual inspection with Acetic Acid (VIA) — HPV testing for high risk HPV types
- #20 , and he subsequently isolated and cloned different strains of HPV. His research concluded that patients infected with HPV types 16 and 18 were at an increased risk of developing cancer.
- #21 Purified L1 protein self-assembles to form empty shells or virus-like particles (VLPs) that resemble a virus.
- #22 Purified L1 protein self-assembles to form empty shells or virus-like particles (VLPs) that resemble a virus.
- #25 Systemic immunization with L1 VLPs generates antibody concentrations 1–4 logs higher than in a natural infection, possibly because of high antigen concentration and deliv- ery route that grants access to lymph nodes and spleen. There is still Strategies such as concatenating multiple L2 proteins boost immunogenicity and show cross-protection against HPVs 16, 18, 45 and 58 pseudovirions.
- #27 Cross- protection from 6-month type-specific persistent infection from non-vaccine types was restricted to HPV 31 for Gardasil® and to HPVs 31,33,52,45 and 51 for Cervarix® in the corresponding naïve cohorts Both vaccines show some degree of cross-protection for both HPV infection and lesions related to non-vaccine types
- #30 Because risk of HPV infection is high within the first few years after onset of sexual activity, assessing risk factors for HPV acquisition (e.g. number of sexual partners, condom use and smoking) before vaccination accurately and confidentially would be challenging and labour intensive, and might substantially reduce coverage.
- #31 Because risk of HPV infection is high within the first few years after onset of sexual activity, assessing risk factors for HPV acquisition (e.g. number of sexual partners, condom use and smoking) before vaccination accurately and confidentially would be challenging and labour intensive, and might substantially reduce coverage.
- #33 because HPV vaccines are non-infectious; the primary target group for HPV vaccines is girls before onset of sexual activity (i.e. before risk of sexual HIV exposure); potential benefits for HIV-infected females at increased risk of HPV-related disease are great; the burden of HPV-related disease is high; and potential benefits of vaccination outweigh potential risks.
- #34 (the vaccination series can be started beginning at age 9 years) Advisory committee for immunization practices
- #35 (the vaccination series can be started beginning at age 9 years) No evidence of impaired fertility or harm to the fetus Advisory Committee on Immunization Practices (ACIP)
- #36 (the vaccination series can be started beginning at age 9 years) no evidence of impaired fertility or harm to the fetus
- #39 Slight variation in the interval do not vary the GMT
- #40 Female can be infected with other HPV type not contained in the vaccine.
- #41 Female can be infected with other HPV type not contained in the vaccine. , as for all males, and vaccination through age 26 years for those who have not been vaccinated previously or who have not completed the 3-dose series.
- #42 Female can be infected with other HPV type not contained in the vaccine. , as for all males, and vaccination through age 26 years for those who have not been vaccinated previously or who have not completed the 3-dose series.
- #43 However, HPV vaccines have not been shown to cause any adverse pregnancy outcomes or adverse events for the mother or her developing fetus. If a woman is found to be pregnant after starting the HPV vaccine series, second and/or third doses should be delayed, and given after she is no longer pregnant. Pregnancy testing is not needed before vaccination. If a pregnant woman does receive HPV vaccine, no intervention is needed. The tip cap of prefilled syringes of HPV2 might contain latex.
- #49 Global alliance on vaccine and immunization Compliance with cervical Pap smear screening is low in India VIA & VILI – remains important tool
- #52 Indian Academy of Pediatrics Committee of Immunization (IAPCOI) 2008 recommendations: “This vaccine has a favorable tolerability profile and the IAP-COI recommends offering HPV vaccine to all females as per label. The recommended age for initiation of vaccination is 10-12 years and catch up vaccination is permitted up to the age of 26 years. It is recommended to be given in three doses at 0, 2 and 6 months.” (Category 2 of IAP categorisation of vaccines)