CepljenjeprotiHPV MarioPoljak Inštitutzamikrobiologijoinimunologijo,MedicinskafakultetaUniverzevLjubljani loveški papilomavirusi (HPV) so zelo heterogena skupina virusov, ki jih povezujemo z nastankom številnih benignih in malignih novotvorb ploš atoceli nega epitelija. Dvanajst onkogenih genotipov HPV (najpomembnejša sta genotipa HPV 16 in HPV 18) je odgovornih za nastanek ve kot 99 % raka materni nega vratu, 84 % raka zadnjika, 70 % raka nožnice, 47 % raka penisa, 40 % raka ženskega zunanjegaspolovila(vulve)ter28%raka ustnega delažrela. Nasprotnoje12 neonkogenihgenotipov HPV (najpomembnejša sta genotipa HPV 6 in HPV 11) odgovornih za nastanek ve kot 95 % genitalnihbradavicinploš atoceli nihpapilomovgrla. V zadnjih nekaj letih sta razvoj in uspešna uvedba profilakti nih cepiv proti HPV omogo ila pomemben napredek v u inkovitemu prepre evanju okužbe s HPV. Trenutno sta na evropskem tržiš u dveprofilakti ni cepivi protiHPV:štirivalentnoindvovalentno.Profilakti nicepivi temeljita na uporabi t. i. virusom podobnih delcev (ang. viral like particles), ki predstavljajo umetno narejene kapside HPV, sestavljene iz rekombinantnih virusnih beljakovin L1. Virusom podobni delci ne vsebujejo virusne DNA, ne morejo okužiti loveških celic, niti se v njih razmnoževati ali povzro ati bolezni. Štirivalentno cepivo vsebuje virusom podobne delce genotipov HPV 6, HPV 11, HPV 16 in HPV 18 in je v EU od septembra 2006 odobreno za prepre evanje nastanka raka materni nega vratu, predrakavih sprememb materni nega vratu, ženskega zunanjega spolovila in nožnice ter anogenitalnih bradavic. U inkovitost štirivalentnega cepiva je bila v za etnih indikacijah v EU omejena le na HPV 6, HPV 11, HPV 16 in HPV 18, od avgusta 2010 je postavljena nekoliko širše in ni ve omejena samo na zaš ito pred cepilnimi genotipi HPV. Znotraj indikacij v EU s štirivalentnim cepivom lahko cepimo osebe ženskega spola od 9. leta starosti dalje, brez zgornje omejitve starosti. Ameriška FDA je štirivalentno cepivo odobrila za oba spola: pri ženskah v starosti 9 26 let za prepre evanještirihrakov:raka materni negavratu, rakaženskega zunanjegaspolovila,raka nožnice 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 43 in raka zadnjika, predrakavih sprememb navedenih rakov (CIN1 3, adenokarcinom in situ, VIN2 3, VaIN2 3, AIN1 3) in anogenitalnih bradavic ter pri moških v starosti 9 26 let za prepre evanje raka zadnjika,predrakavih sprememb zadnjika (AIN1 3)teranogenitalnihbradavic.Ameriška FDAomejuje u inkovitost štirivalentnega cepiva pri obeh spolih na HPV 6, HPV 11, HPV 16 in HPV 18. Osnovno cepljenje s štirivalentnim cepivom se izvaja s tremi posameznimi odmerki cepiva po shemi 0., 2., 6. mesec. Dvovalentno cepivo vsebuje virusom podobne delce genotipov HPV 16 in HPV 18 in je v EU od septembra 2007 odobreno za prepre evanje raka materni nega vratu in predrakavih sprememb materni negavratu(CIN1 3,adenokarcinominsitu).U inkovitostdvovalentnegacepivajebilavEUv za etnihindikacijahomejenalenaHPV 16inHPV 18,odavgusta2010jepostavljenanekolikoširšein ni ve omejena samo na zaš ito pred cepilnimi genotipi HPV. Znotraj indikacije v EU lahko cepimo osebe ženskega spola v starosti od 10 do 25 let. Ameriška FDA je odobrila enake indikacije za dvovalentno cepivo kot EMA, vendar omejuje u inkovitost cepiva na HPV 16 in HPV 18. Osnovno cepljenje z dvovalentnim cepivom se izvaja s tremi posameznimi odmerki cepiva po shemi 0., 1., 6. mesec. Do marca 2011 je bilo z obema HPV cepivoma cepljenih ve kot 50 milijonov ljudi. Idealni as cepljenja proti HPV je obdobje pred prvimi spolnimi odnosi in ni neposredno vezan na starost. Glede nato,da cepljenješ itipredvsempredboleznimi, kijihpovzro ajo genotipivirusa,vklju enivcepivo, je pri cepljenih ženskah zaenkrat treba izvajati presejalne preglede za odkrivanje predrakavih sprememb materni nega vratu v enakem obsegu in na enak na in kot pri necepljenih. Cepivi proti HPV nimata nobenega merljivega terapevtskega u inka in zato nista indicirani za zdravljenje raka materni negavratuindrugihsHPVpovezanihrakovalizazdravljenjeinprepre evanjenapredovanja predrakavih sprememb materni nega vratu, ženskega zunanjega spolovila, nožnice in zadnjika. Razvoj profilakti nih cepiv proti HPV druge generacije temelji na vklju evanju ve jega nabora genotipov HPV, nižanju njihove cene, ve anju temperaturne obstojnosti cepiva ter enostavnejši aplikaciji(npr.transdermalnaaliintranazalnaaplikacija). 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 44 Mario Poljak Inštitut za mikrobiologijo in imunologijo Medicinska fakulteta, Univerza v Ljubljani Cepljenje proti HPV high-risk HPV genotypes (12) 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 Bouvard V et al. A review of human carcinogens - Part B: biological agents. Lancet Oncol. 2009;10:321-2. 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 96 low-risk HPV genotypes (12) 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP6108 MSD GSK Silgard™, Gardasil™ Cervarix™ Quadrivalent vaccine Bivalent vaccine HPV-6, HPV-11, HPV-16, HPV-18 HPV-16, HPV-18 Expression system Yeast (Saccharomyces cerevisiae) Insect cells (baculovirus) Composition (quant.) 20 µg HPV-6 L1 protein 20 µg HPV 16 L1 protein 40 µg HPV-11 L1 protein 20 µg HPV 18 L1 protein 40 µg HPV-16 L1 protein 20 µg HPV-18 L1 protein Adjuvant Aluminum hydroxyphosphate sulfate AS04 Dose and administration 0.5 ml, intramuscular 0.5 ml, intramuscular Schedule 0, 2, and 6 months 0, 1, and 6 months EMA FDA Status: 02 April 2011 GARDASIL is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine: - cervical, vulvar, vaginal, and anal cancer caused by HPV types 16 and 18 - genital warts (condyloma acuminata) caused by HPV types 6 and 11 and the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18: - cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ (AIS) - cervical intraepithelial neoplasia (CIN) grade 1 - vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3 - vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3 - anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 Gardasil is a vaccine for use from the age of 9 years for the prevention of: – premalignant genital lesions (cervical, vulvar and vaginal) and cervical cancer causally related to certain oncogenic Human Papillomavirus (HPV) types – external genital warts (condyloma acuminata) causally related to specific HPV types. See sections 4.4 and 5.1 for important information on the data that support this indication. 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 97 EMA FDA Status: 02 April 2011 GARDASIL is indicated in boys and men 9 through 26 years of age for the prevention of the following diseases caused by HPV types included in the vaccine: - anal cancer caused by HPV types 16 and 18 - genital warts (condyloma acuminata) caused by HPV types 6 and 11 and the following precancerous or dysplastic lesions caused by types 6, 11, 16, and 18: - nal intraepithelial neoplasia (AIN) grades 1, 2, and 3. MSD GSK Silgard™, Gardasil™ Cervarix™ Quadrivalent vaccine Bivalent vaccine HPV-6, HPV-11, HPV-16, HPV-18 HPV-16, HPV-18 Expression system Yeast (Saccharomyces cerevisiae) Insect cells (baculovirus) Composition (quant.) 20 µg HPV-6 L1 protein 20 µg HPV 16 L1 protein 40 µg HPV-11 L1 protein 20 µg HPV 18 L1 protein 40 µg HPV-16 L1 protein 20 µg HPV-18 L1 protein Adjuvant Aluminum hydroxyphosphate sulfate AS04 Dose and administration 0.5 ml, intramuscular 0.5 ml, intramuscular Schedule 0, 2, and 6 months 0, 1, and 6 months EMA FDA Status: 02 April 2011 CERVARIX is a vaccine indicated for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18: - cervical cancer - cervical intraepithelial neoplasia (CIN) grade 2 or worse and adenocarcinoma in situ - cervical intraepithelial neoplasia (CIN) grade 1. CERVARIX is approved for use in females 10 through 25 years of age. Cervarix is a vaccine for the prevention of - premalignant cervical lesions and cervical cancer causally related to certain oncogenic Human Papillomavirus (HPV) types. See sections 4.4 and 5.1 for important information on the data that support this indication. The indication is based on the demonstration of efficacy in women aged 15-25 years following vaccination with Cervarix and on immunogenicity of the vaccine in girls and women aged 10-25 years. 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 98 Conclusion: Prophylactic HPV vaccines are safe, well tolerated, and highly efficacious in preventing persistent infections and cervical diseases associated with vaccine-HPV types among young females. 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 99 4703 case reports of suspected ADRs for Cervarix between 14/4/2008–28/7/2010, out of at least 4.5 million doses given across the UK (around 1 report per 1000 doses) - 17% injection-site reactions - 11% allergic reactions - 37% side effects listed in the product information (dizziness, headache and nausea) - 21% psychogenic’ reactions, due to the injection process rather than the vaccine itself no serious new risks identified during the extensive use of Cervarix in the UK over 2 years balance of Cervarix benefits and risks remains positive Dorleans F, Giambi C, Dematte L, et al. The current state of introduction of human papillomavirus vaccination into national immunisation schedules in Europe: first results of the VENICE2 2010 survey. Euro Surveill. 2010;15(47):pii=19730. Dorleans F, Giambi C, Dematte L, et al. The current state of introduction of human papillomavirus vaccination into national immunisation schedules in Europe: first results of the VENICE2 2010 survey. Euro Surveill. 2010;15(47):pii=19730. 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 100 Prophylactic HPV vaccines- Unresolved issues I What fraction of cervical cancer overall will be prevented ? Cross-protection ? Will booster vaccinations be necessary, and if so, when ? TIME WILL TELL Prophylactic HPV vaccines- Unresolved issues II Which vaccine is better ? - considerable marketing efforts have been made to compare the two vaccines in relation to the HPV 16 and HPV 18 components - markedly different populations/subpopulations were used in each of the vaccine trials - direct comparison of trials’ results impossible 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 101 Prophylactic HPV vaccines – unresolved issues III Completion of the HPV vaccine schedule & small coverage - at least 80% of pre-adolescent girls need to be vaccinated against HPV to achieve a major reduction in cervical cancer rates in women aged 20–29 years by 2025 - great majority of countries are struggling to achieve high coverage and/or to reach the level of coverage that will have the most impact on cancer rates Prophylactic HPV vaccines – unresolved issues IV Improving girls’/parents/medical workers understanding of HPV infection & vaccination Prophylactic HPV vaccines – unresolved issues V HPV vaccination of women aged 26 years & above HPV vaccination of males - until there is high HPV vaccine coverage among targeted groups, broadening the population eligible for (free) vaccination should be approached with caution - it is important to maintain clarity about the primary purpose of HPV vaccination and to ensure that information, delivery systems and finances are in place to achieve that purpose - vaccination of men or older women could offer individual benefit but this may confuse the public, which is already unclear about age selection 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 102 Prophylactic HPV vaccines – unresolved issues VI - given the likely absence of further large Phase III clinical trials, it is extremely important that countries with national vaccination programs comprehensively evaluate long-term safety and any breakthrough infections of HPV vaccine types over the short and longer term - linkage of vaccination history and cervical screening history is necessary Monitoring of long-term safety and vaccine disease efficacy Prophylactic HPV vaccines – unresolved issues VII - a clear strategy for integrating primary (HPV vaccination) and secondary prevention (cervical screening/HPV testing) must emerge ASAP - cervical screening guidelines have to be reviewed in the next 5-10 years - there is an increasing acceptance that screening based on HPV testing would be better than continuing with cytology as the primary screen Integration of primary & secondary cervical cancer prevention Prophylactic HPV vaccines – unresolved issues VIII The price of HPV vaccine MUST go down substantially ! it would NOT be a satisfactory outcome if HPV vaccines are proven to be safe and effective but are not made available to the women of the world who are most in need of them 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 103 HPV Prophylactic Vaccines – second generation - polyvalent VLP L1 vaccines -L 1 c a p s o m e r s (pentameric subunit of VLP) - VLP L2 vaccines - new adjuvants-based vaccines 2.izobraževalnidanprogramaZORA,april2011 _______________________________________ 104