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Squarzon, Laura (2013) Evaluation of HPV type-specific antibody response induced by the prophylactic quadrivalent vaccine. [Ph.D. thesis]

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Abstract (english)

Human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide and affects approximately 300 million new individuals each year. HPV is considered the primary etiological agent involved in the development of cervical cancer and causes half a million cases per year worldwide. Prevention of genital HPV infection through immunization has led investigators to employ a number of strategies to develop candidate HPV vaccines. Until today, two different vaccines are available on the market: a quadrivalent vaccine that protects against HPV types 16, 18, 6, and 11 (Gardasil®, Merck Sharp and Dohme), and a bivalent vaccine that protects against HPV types 16 and 18 (Cervarix™, Glaxo SmithKline). Current data regarding the efficacy of these vaccines derive mainly from studies performed by the manufacturers and standardized assays are not commercially available to measure HPV immunity.
In this context, the aim of this PhD research project is to set up and standardize HPV pseudovirion-based neutralization (PBNA) and enzyme-linked immunosorbent (ELISA) assays and to use these tests to evaluate and compare the immunogenicity and cross-reactivity levels of the two prophylactic HPV vaccines, which are offered free in Italy to 12-year old girls and are recommended to women aged 12-45 years, according to World Health Organization (WHO) guidelines.
First, pseudovirions of HPV types 6, 11, 16, 18, 31, 45, 52, 58 were obtained with a titer of 109 transducing units/ml and neutralization and ELISA assays standardized. Subsequently, a cross sectional study to evaluate the humoral immune response against HPV-volunteers, adolescents, and healthy vaccinated adults with Gardasil® or Cervarix™ was approved by ethics committee of University Hospital of Padua. Comprehensive results were obtained from a group of 100 subjects from Veneto Region, where the quadrivalent Gardasil® vaccine was offered. The study group included 81 subjects investigated within 1-6 months after the completion of the three doses of vaccine and 7, 7, and 5 subjects investigated at 2, 3, and 4 years after vaccination, respectively.
At 1-6 months after the completion of the vaccination cycle, 100% vaccinees had neutralizing antibodies (NAbs) against HPV16, 98,8% had NAbs against HPV18, while 91% had NAbs against HPV6 and 50% had NAbs against HPV11. The NAbs titer ranged widely from 1:40 to over 1:10,240 and was lower for NAbs against HPV6 and HPV11 as compared with NAbs titers against HPV16 and HPV18. A progressive reduction of NAbs titer was observed over time and, at 4 years from vaccination, 80% of subjects had NAbs against HPV16, HPV18 and HPV6, and 60% against HPV11. Low level cross-NAbs titer against HPV31 (1:40) was detected in 50% (3/6) of subjects at 1-6 months after vaccination, while no cross-NAbs were detected against HPV45, HPV52 and HPV58.
We also evaluated the presence of HPV type-specific NAbs in a group of 6 young girls vaccinated with CervarixTM at 1-6 months after the completion of the vaccination cycle. All subjects presented specific NAbs against HPV16 and HPV18. Titers were higher as compared with titers observed in Gardasil® vaccinated subjects. 100% of subjects presented also cross-NAbs against HPV31, whereas 16,6% presented cross-NAbs against HPV45 and HPV58. None presented cross-NAbs against HPV52.
Thanks to these results we can conclude that high-level NAbs were induced with both Gardasil® and CervarixTM vaccines. For the first vaccine, we observed the decline of NAbs titers and the limited cross-neutralization against HPV31. For the second one, cross-neutralizing NAbs were observed against HPV31 in all subjects, together with the presence of NAbs against HPV45 and HPV58 in some subjects.

Abstract (italian)

L'infezione da papilloma virus umano (HPV) è una delle più comuni infezioni trasmesse per via sessuale in tutto il mondo e colpisce circa 300 milioni di nuovi individui ogni anno. L’infezione persistente da tipi di HPV definiti ad alto rischio è la causa necessaria per lo sviluppo del cancro del collo dell’utero. Annualmente, vengono registrati circa 500.000 casi di carcinomi del collo dell’utero in tutto il mondo. La necessità di prevenire questo tipo di infezione ha portato nel corso degli ultimi anni allo sviluppo di diverse strategie vaccinali. Ad oggi, sono disponibili due diversi vaccini profilattici: un vaccino quadrivalente che protegge contro HPV16, 18, 6, e 11 (Gardasil®, Merck Sharp & Dohme), e un vaccino bivalente che protegge contro HPV 16 e 18 (Cervarix™, Glaxo SmithKline). I dati riguardanti l'efficacia e l’immunogenicità di questi due vaccini derivano principalmente da studi effettuati dalle ditte produttrici. Non sono disponibili inoltre test standardizzati commerciali in grado di valutare l'immunità nei confronti dei diversi tipi di HPV.
Obiettivo di questo progetto di ricerca di dottorato è quello di sviluppare e standardizzare un test specifico per la ricerca di anticorpi anti-HPV basato sulla neutralizzazione di diversi tipi di HPV mediante pseudovirioni (PBNA) e un test immunoenzimatico (ELISA), e di utilizzare questi test per valutare e confrontare i livelli di immunogenicità e cross-reattività dei due vaccini profilattici anti-HPV che sono offerti gratuitamente in Italia alle ragazze nel loro dodicesimo anno di età e che vengono raccomandati per le donne di età compresa tra i 12 e i 45 anni, secondo le linee guida dell'Organizzazione Mondiale della Sanità (OMS).
A tal fine, sono stati prodotti diversi lotti di pseudovirioni corrispondenti ai tipi HPV6, 11, 16, 18, 31, 45, 52, 58 con un titolo pari a 109 unità trasducenti/ml e sono stati standardizzati i saggi di neutralizzazione tipo-specifica e il saggio ELISA. E’ stato disegnato uno studio cross-sectional per valutare la risposta immunitaria umorale contro i diversi tipi di HPV in soggetti sani, adolescenti e adulti, vaccinati con Gardasil® o Cervarix™.
I risultati sono stati ottenuti analizzando un gruppo di 100 soggetti della Regione Veneto, dove era offerta la vaccinazione con Gardasil®. In particolare, sono stati esaminati 81 soggetti a distanza di 1-6 mesi dal completamento del ciclo vaccinale, 7 soggetti valutati a 2 anni dalla vaccinazione, 7 soggetti a 3 anni dalla vaccinazione, e 5 a 4 anni dalla vaccinazione.
A distanza di 1-6 mesi dal completamento della vaccinazione con Gardasil®, il 100% dei soggetti presentava anticorpi neutralizzanti contro HPV16, il 98,8% contro HPV18, il 91% contro HPV6 e il 50% contro HPV11. Sono stati ottenuti titoli di anticorpi neutralizzanti compresi tra 1:40 e 1:10,240. I titoli osservati nei confronti di HPV6 e HPV11 sono risultati inferiori rispetto a quelli osservati nei confronti di HPV16 e HPV18. E’ stata, inoltre, osservata una riduzione progressiva nel titolo in base al tempo intercorso dall’ultima dose vaccinale. A 4 anni dalla vaccinazione, l'80% dei soggetti presentava anticorpi neutralizzanti contro HPV16, HPV18 e HPV6, mentre il 60% nei confronti di HPV11. Per quanto riguarda la presenza di anticorpi cross-neutralizzanti, è stato osservato un titolo pari a 1:40 nei confronti di HPV31 nel 50% (3/6) dei soggetti entro i primi 6 mesi dalla vaccinazione, mentre non sono stati rilevati anticorpi cross-neutralizzanti nei confronti di HPV45, HPV52 e HPV58.
E' stata valutata, inoltre, la presenza di anticorpi neutralizzanti nei confronti dei diversi tipi di HPV in un gruppo di 6 ragazze vaccinate con CervarixTM a distanza di 1-6 mesi dal completamento della vaccinazione. Tutti i soggetti presentavano anticorpi neutralizzanti nei confronti di HPV16 e HPV18, a titoli più elevati rispetto ai titoli osservati nei soggetti vaccinati con Gardasil®. Il 100% dei soggetti presentava, inoltre, anticorpi cross-neutralizzanti contro HPV31, mentre il 16,6% aveva anticorpi cross-neutralizzanti contro HPV45 e HPV58. Nessun soggetto ha presentato anticorpi cross-neutralizzanti contro HPV52.
In conclusione, entrambi i vaccini sono in grado di indurre elevati livelli di specifici anticorpi neutralizzanti i tipi di HPV vaccinali. Per quanto riguarda il vaccino Gardasil® è stata osservata una diminuzione dei titoli anticorpali nel tempo e una limitata cross-neutralizzazione nei confronti di HPV31. Per quanto riguarda il vaccino CervarixTM, invece, è stata osservata la presenza di anticorpi cross-neutralizzanti contro HPV31 in tutti i soggetti, unitamente alla presenza degli anticorpi neutralizzanti contro HPV45 e HPV58 in alcuni soggetti.

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EPrint type:Ph.D. thesis
Tutor:Barzon, Luisa
Ph.D. course:Ciclo 25 > Scuole 25 > BIOMEDICINA
Data di deposito della tesi:27 January 2013
Anno di Pubblicazione:27 January 2013
Key Words:Papillomavirus umano, vaccino, risposta anticorpale, HPV, Human papillomavirus, vaccine, antibody response
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/07 Microbiologia e microbiologia clinica
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:5540
Depositato il:11 Oct 2013 15:36
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