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Mantelli, Barbara (2014) Valutazione delle risposte immunitarie umorali e cellulari di tipo B in soggetti vaccinati con Gardasil o Cervarix. [Tesi di dottorato]

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Abstract (inglese)

The family of human papillomaviruses comprises over 120 different types that infect cutaneous and mucosal tissues, and among them high-risk genotypes (HPV16, 18, 31, 33, 45, 51, 58 and others) are strongly associated with different cancer in the genital tract in men and women. Low-risk genotypes (HPV6, 11, 40, 43 and others) are found in genital epithelial lesions but rarely detected in malignancies.
Cervical cancer is the third most common cancer in women world-wide associated with persistent infection of sexually transmitted high-risk HPV genotypes. In particular, HPV16 and 18 cause more than 70% of invasive cervix cancer in women. Immunocompetent women are able to clear high-risk HPV genotypes infections in 12-18 months. This is accompanied or closely followed by seroconversion against the major coat protein L1. The antibody titres developed during natural infection are low and don’t protect against HPV reinfection, moreover, not all women seroconvert. Approximately 10% of women fail to clear HPV infection resulting in long-term persistent infection that leads to progressive disease.
In 2006-2007 two prophylactic vaccines were licenced based on virus-like particles technology: a bivalent HPV16/18 L1 VLP vaccine (Cervarix, GSK) and a tetravalent HPV 6/11/16/18 L1 VLP vaccine (Gardasil, MSD). Both vaccines showed almost 100% efficacy against CIN 2/3 against vaccine-related HPV types in naïve women. The efficacy is considerably lower against HPV types not included in vaccine formulation, and also in women with evidence of previous or current infections of vaccine-related genotypes. Furthermore, both vaccines are safe, and induce high titres of type-specific neutralizing antibodies against both linear and conformational epitopes on capsid protein L1 (4 years follow up of phase III clinical trials) preventing both high risk HPV16 and 18 infection and lesion development in the cervix. In addition, the quadrivalent vaccine is protective against occurrence of external genital warts.
Despite this success, several key issues are still open. In fact, reports from phase III studies suggest that the two HPV vaccines may induce different antigen-specific immune responses in terms of intensity and persistence. The generation of memory B-cells and their responses to recall antigens are crucial factors for the long-term efficacy of vaccine induced humoral protection and up to now standardized assays are not commercially available to measure HPV immunity. Moreover, the efficacy in pre- and early adolescents, the primary targets for vaccination, has not been demonstrated. Furthermore, at present, the majority of data available on the two HPV vaccines comes from studies performed by the manufacturers.
In this contest, an independent study was designed by enrolling HPV vaccinated women in Veneto and Emilia Romagna Regions to a) set up standardized B-cell elispot assays to measure the frequency of memory B-cells specific to HPV6, 11, 16 and 18 VLPs; b) screen a cohort of HPV vaccinees stratified by age (12 years old vs 20-45 years old) and by time after the 3rd dose of vaccine (1-6 months vs 4 years); c) compare the immune responses of Cervarix and Gardasil HPV vaccines.
This study demonstrates that Gardasil induces high and sustained number of memory B-cells against the HPV types included in the vaccine formulation. With regard to the frequency of memory B-cells the vaccine was not influenced by the age of vaccine administration and was similar among the age groups at 1-6 months and 4 years after vaccination. Furthermore, Gardasil induces high antigen-specific IgG titres in both age groups that decrease significantly 4 years after vaccination but remains still detectable. However, the IgG titres were significantly lower in the 20-45 years old group compared to the 12 years old group both both 1-6 months and 4 years after vaccination, and the percentage of vaccinees whom IgG levels were still detectable were significantly lower in the 20-45 years old group compared to the 12 years old group 4 years after the vaccination.
Cervarix induces higher B-cell responses (both frequency of memory B-cells and antigen-specific IgG titres) compared to Gardasil in 12 years old vaccinees, tested 1-6 months after vaccination. Evalutation of immune responses in 12-years old Cervarix recipients 4 years after vaccination as well as in 20-45 years old (both 1-6 months and 4 years after vaccination) is in progress.

Abstract (italiano)

Il carcinoma della cervice uterina rappresenta la seconda causa di morte per tumore tra le giovani donne fra i 15 e i 44 anni, dopo il tumore al seno. Si stimano infatti a livello mondiale 530.000 nuovi casi di tumore cervicale all’anno e circa 275.000 decessi. Lo sviluppo del tumore alla cervice uterina è imputabile all’infezione persistente, sessualmente trasmessa, di alcuni genotipi ad alto rischio di Papillomavirus (HPV); in particolare più del 70% di tutti i tumori cervicali è correlato con la presenza di HPV16 e 18 mentre il rimanente 25% è legato all’infezione causata da altri genotipi di HPV come 31, 33, 45 e 58.
Le donne immunocompetenti sono in grado di eliminare spontaneamente le infezioni dei genotipi ad alto rischio in 12-18 mesi. La seroconversione che deriva dall’infezione non avviene in tutte le donne e, laddove succede, i titoli degli anticorpi neutralizzanti sono molto bassi e non proteggono da successive reinfezioni. Inoltre, il 10% delle donne non è in grado di eliminare il virus e l’infezione persistente a livello della mucosa cervicale, è il punto di partenza di una serie di eventi molecolari che portano allo sviluppo di lesioni neoplastiche.
Nel 2006-2007 sono stati approvati e commercializzati due vaccini profilattici anti-HPV costituiti dalle proteine L1 del capside virale, assemblate a formare degli pseudovirioni (VLP) tridimensionalmente identici alle particelle virali native ma non infettivi: Cervarix (GSK) contenente le VLP di HPV16 e 18 e Gardasil (Merck) contenente le VLP di HPV6, 11, 16 e 18, quindi protettivo anche nei confronti di infezioni genitali di tipo benigno come i condilomi.
Gli studi clinici hanno dimostrato che entrambi i vaccini sono sicuri, capaci di indurre elevati livelli di anticorpi neutralizzanti contro la proteina L1 ed efficaci nel proteggere dall’infezione da parte dei genotipi di HPV presenti nel vaccino. Tuttavia, i vaccini sono in commercio solo da pochi anni e sono necessari ulteriori studi per correlare l’efficacia di protezione con l’entità delle risposte immunitarie indotte. Per studiare l’immunità a lungo termine, la determinazione dei titoli anticorpali (neutralizzanti e non) è uno strumento utile ma non sufficiente, ed è necessario quindi quantificare i linfociti B memoria antigene-specifici. Inoltre, sono ancora pochi i dati disponibili in letteratura sull’induzione delle risposte immunitarie in funzione dell’età di somministrazione del vaccino e soprattutto la maggior parte dei dati di efficacia e di risposte immunitarie indotte da Gardasil e Cervarix provengono dalle aziende che commercializzano i vaccini.
In questo contesto, lo studio indipendente da noi eseguito aveva tre obiettivi: 1) sviluppare e standardizzare una metodica di B-cell Elispot per la quantificazione dei linfociti B memoria HPV genotipo-specifici; 2) quantificare i linfociti B memoria e i titoli anticorpali, specifici per ciascun antigene vaccinale, in una popolazione di adolescenti (12 anni) e di donne (20-45 anni) vaccinate con Gardasil o Cervarix, arruolate 1-6 mesi o 4 anni dopo la vaccinazione; 3) comparare l’immunogenicità dei due vaccini anti-HPV. In particolare, ad oggi sono state arruolate 283 volontarie di cui per il vaccino Gardasil n=121 per il gruppo 12 anni, n=112 per il gruppo 20-45 anni e per il vaccino Cervarix n=60 per il gruppo 12 anni. L’arruolamento dei soggetti vaccinati con Cervarix è ancora in corso e lo studio verrà completato nei prossimi 6 mesi.
I risultati dello studio hanno dimostrato che le frequenze dei linfociti B memoria HPV genotipo-specifiche indotte dal Gardasil sono elevate 1-6 mesi dopo la vaccinazione in entrambe le coorti di età e, nonostante diminuiscano nel corso del tempo, dopo 4 anni continuano ad essere significativamente elevate indipendentemente dall’età di somministrazione del vaccino. Al contrario, i titoli anticorpali sono influenzati dall’età di somministrazione del vaccino. Infatti, i titoli anticorpali misurati nella coorte di adolescenti sono sempre significativamente superiori rispetto a quelli misurati nella corte delle donne, sia 1-6 mesi sia 4 anni dopo la vaccinazione. In aggiunta, la percentuale di individui i cui titoli anticorpali non sono più misurabili, dopo 4 anni dalla vaccinazione, è significativamente superiore nelle donne rispetto alle adolescenti.
Relativamente alla comparazione delle risposte immunitarie indotte dai due vaccini anti-HPV, i risultati preliminari ottenuti in un gruppo di adolescenti vaccinate con Cervarix dimostrano che 1-6 mesi dopo la vaccinazione il Cervarix induce titoli anticorpali e frequenze di linfociti B memoria anti-HPV16 e 18 significativamente superiori rispetto ad adolescenti vaccinate con Gardasil.
I risultati ottenuti potranno essere un utile ausilio per il Ministero della Salute per tracciare le linee guida di prevenzione primaria del tumore alla cervice uterina.

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Tipo di EPrint:Tesi di dottorato
Relatore:Palù, Giorgio - Caputo, Antonella
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > BIOMEDICINA
Data di deposito della tesi:28 Gennaio 2014
Anno di Pubblicazione:Gennaio 2014
Parole chiave (italiano / inglese):B-cell Elispot HPV Gardasil Cervarix Cellule B memoria ELISA
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/07 Microbiologia e microbiologia clinica
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:6433
Depositato il:19 Mag 2015 17:41
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