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Agnolon, Valentina (2015) A formulation science perspective applied to combination vaccines: particles-based multiplex immunoassays for improved antigens characterization and rational design of adjuvants for tailored immunity to acellular pertussis vaccines. [Tesi di dottorato]

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Abstract (inglese)

Summary:
Vaccines are complex multi-component products, in which an interdependent relationship among constituents exists: the concomitant inclusion of antigens, adjuvants, and excipients is essential to guarantee the efficacy of the final product. To stimulate the immune system and raise immunogenicity against highly purified vaccine components most likely adjuvants are required, thus becoming more and more crucial elements of modern vaccine formulations. Physico-chemical and functional attributes of all components and of the whole vaccine formulation have to be controlled before injection. However, often characterization challenges are experienced with the currently available analytical techniques, also because of interferences with adjuvants.
In this thesis adjuvants were evaluated with the aim to improve quality and immunogenicity of combination vaccines, in which the inclusion of multiple antigenic components contributes to enhanced complexity of the final product.
In detail, three virulence factors of the Gram negative bacterium Bordetella pertussis (pertussis toxin PT, filamentous heamagglutinin FHA, and pertactin 69K) were chosen as model antigens. Currently licensed acellular pertussis (aP) vaccines are combined with diphtheria and tetanus toxoids in the DTaP/TdaP vaccine, which is considered a cornerstone of combination vaccines. This vaccine is typically adjuvanted with aluminum salts, known to induce mainly a humoral immune response which has been associated with recent pertussis outbreaks reported in many countries. This suggests that existing vaccines may not be ideal to provide protection against the disease. Thus, a pharmaceutical sciences approach focusing on adjuvants was applied to investigate the potential improvement of acellular pertussis vaccines through promotion of the analytical characterization and rational polarization of the quality of immune responses.

Improved in vitro characterization assays for combination vaccines adjuvanted with aluminum hydroxide:
Vaccines in vitro characterization is required to identify optimal formulation conditions to ensure physical, chemical, and biological integrity of antigens and adjuvants. Analytical methods currently in use are mostly suitable for the characterization of unformulated antigens – requiring the complete desorption from aluminum-based adjuvants - and are not always able to reveal individual antigens in vaccine combinations. Here, the Luminex technology is proposed as proof of concept for the development of an improved analytical method for vaccine characterization, based on the use of specific antibodies bound to magnetic microspheres presenting unique digital signatures for simultaneous recognition of respective antigens in the entire formulation. TdaP combination vaccines were chosen as a model to develop an assay able to quantify acellular pertussis antigens and their levels of adsorption to adjuvant at the same time. This assay was directly applicable on the commercial vaccine product, avoiding any laborious procedures for separation of the antigens from the adjuvant. Accurate and reproducible quantification of aP antigens in TdaP vaccine has been achieved in a range between 0.78 and 50 ng/mL, providing information on antigen identity, quantity, and degree of adsorption to aluminum hydroxide. Importantly, the Luminex characterization method has the potential to be further evaluated as correlate of in vitro potency assays - ideally allowing reducing in vivo animal studies.

In vivo evaluation of novel adjuvants for improved aP-containing combination vaccines:
The successful approach of combining diphtheria, tetanus and pertussis antigens into a single vaccine has become the cornerstone of pediatric and adults immunization programs. Yet, even if vaccination coverage is high, a resurgence of pertussis has been recently reported in many countries suggesting that current vaccines may not provide adequate long-lasting protection.
In order to develop pertussis-containing vaccines able to induce a more durable and better tailored immune response different approaches have been proposed, including the use of novel adjuvants. Currently licensed pertussis vaccines contain aluminum salts, which are the most common adjuvants for human use. By inducing mainly humoral immune responses aluminum salts might not be ideal for providing protection against pathogens which require a more cellular immune response, such as Bordetella pertussis.
Therefore, alternative adjuvants that induce more balanced T-helper profiles or even Th1-prone responses might be more adequate. In this project, we tested three different adjuvants: MF59 emulsion adjuvant – that induces a mixed Th1/2 response - as well as the combination of a Toll-Like Receptor 4 agonist (TLR4a) or a Toll-Like Receptor 7 agonist (TLR7a) with aluminum hydroxide to induce even further Th1 polarization. The adjuvants were evaluated for their ability to improve immune responses against a TdaP vaccine containing three B. pertussis antigens: genetically detoxified pertussis toxin (PT-9K/129G), filamentous hemagglutinin (FHA) and pertactin (69K).
The quicker onset of serum antibody titers and the changed quality of the antibody responses induced by the adjuvants evaluated here fully support the potential replacement of aluminum salts with alternative adjuvants to enhance pertussis immunogenicity in aP-containing combination vaccines.

Conclusions:
Overall, the collected results suggested the possibility to modulate quality and efficacy of a complex vaccine product by carefully working on the adjuvant component. Improving the analytical characterization of vaccines while addressing a rational polarization of immune responses are proposed as effective strategies to be pursued for the development of next generation combination vaccines.

Abstract (italiano)

Riassunto:
I vaccini sono prodotti complessi costituiti da diversi elementi tra i quali esiste un rapporto d’interdipendenza: la presenza concomitante di antigeni, adiuvanti, ed eccipienti è essenziale per garantire l'efficacia del prodotto finale. Gli adiuvanti sono spesso necessari per stimolare il sistema immunitario e aumentare l'immunogenicità di un vaccino composto di antigeni molto purificati: diventano perciò sempre più importanti nelle moderne formulazioni di vaccini. Le proprietà fisico-chimiche di tutti gli elementi e dell'intera formulazione e devono essere controllate prima dell'iniezione. Tuttavia, le tecniche analitiche ora disponibili spesso interferiscono con gli adiuvanti, e problemi di caratterizzazione sono incontrati.
In questa tesi gli adiuvanti sono stati sfruttati con l'obiettivo di indagare la possibilità di migliorare la qualità e l'immunogenicità dei vaccini combinati, nei quali l'inclusione di più elementi antigenici contribuisce alla maggiore complessità del prodotto finale.
In particolare, tre fattori di virulenza del batterio Gram negativo Bordetella pertussis (tossina della pertosse PT, emoagglutinina filamentosa FHA, e pertactina 69K) sono stati scelti come antigeni modello. I vaccini acellulari di pertosse (aP) attualmente autorizzati sono combinati con le tossine inattivate di difterite e tetano nel vaccino DTaP/TdaP, che è considerato la pietra miliare dei vaccini combinati. Questo vaccino è tipicamente adiuvato con sali di alluminio, noti per indurre prevalentemente una risposta immunitaria umorale che è stata associata con le recenti epidemie di pertosse segnalate in molti paesi. Ciò suggerisce che il vaccino esistente non sia ideale per fornire una protezione contro la malattia. Pertanto, un approccio basato sulle scienze farmaceutiche e focalizzato sugli adiuvanti è stato applicato per studiare il potenziale miglioramento dei vaccini acellulari di pertosse, attraverso lo sviluppo della caratterizzazione analitica e la razionale polarizzazione della qualità della risposta immunitaria.

Sviluppo di saggi di caratterizzazione in vitro per vaccini combinati adiuvantati con idrossido di alluminio:
La caratterizzazione analitica in vitro è necessaria per individuare le condizioni di formulazione ottimali che garantiscano l'integrità fisica, chimica e biologica di antigeni e adiuvanti. I metodi analitici ora in uso sono soprattutto adatti per la caratterizzazione di antigeni non formulati - richiedendo quindi il desorbimento completo dalla superfice degli adiuvanti a base di alluminio - e non sempre sono in grado di distinguere tra i singoli antigeni contenuti nei vaccini combinati. In questa tesi la tecnologia Luminex è proposta come proof of concept per lo sviluppo di un miglior metodo analitico per la caratterizzazione di vaccini. Questo metodo è basato sull'utilizzo di anticorpi specifici legati a microsfere magnetiche che sono univocamente riconoscibili tramite una firma digitale permettendo quindi l’identificazione simultanea dei rispettivi antigeni formulati nel vaccino.
I vaccini combinati TdaP sono stati scelti come modello per sviluppare un saggio in grado di quantificare simultaneamente gli antigeni acellulari della pertosse (aP) e il loro grado di adsorbimento all’adiuvante. Questo saggio è direttamente applicabile al vaccino commerciale, evitando qualsiasi procedura laboriosa per la separazione degli antigeni dall’adiuvante. Una quantificazione accurata e riproducibile degli antigeni aP nel vaccino TdaP è stata ottenuta in un intervallo di concentrazioni compreso tra 0,78 e 50 ng/mL, fornendo informazioni sull'identità degli antigeni, la loro quantità e il grado di assorbimento alla superficie dell’idrossido di alluminio. Il metodo di caratterizzazione sviluppato sulla tecnologia Luminex ha la potenzialità di essere valutato come test di in vitro potency - permettendo idealmente la riduzione degli studi effettuati sugli animali.

Valutazione in vivo di nuovi adiuvanti per migliorare i vaccini combinati contenenti aP:
L'approccio di combinare gli antigeni di difterite, tetano e pertosse in un unico vaccino è diventato il fondamento dei programmi d’immunizzazione pediatrici e per adulti. Nonostante l’elevata copertura vaccinale, una riacutizzazione dei casi di pertosse è stata recentemente registrata in molti paesi, suggerendo che i vaccini attuali non possono fornire un’adeguata protezione di lunga durata.
Diversi approcci sono stati proposti al fine di sviluppare vaccini in grado di indurre una risposta immunitaria più durevole e più adeguata contro la pertosse, tra cui l'uso di nuovi adiuvanti. I vaccini contro la pertosse ora autorizzati contengono sali di alluminio, che sono gli adiuvanti più comuni per uso umano. Inducendo principalmente risposte immunitarie umorali, i sali di alluminio non sono ideali per fornire protezione contro gli agenti patogeni che richiedono una risposta immunitaria cellulare, come ad esempio Bordetella pertussis.
Pertanto, altri adiuvanti che stimolino l’induzione di cellule Th1 potrebbero essere più adeguati. In questo progetto, abbiamo provato tre diversi adiuvanti: l’emulsione MF59 - che induce una risposta mista Th1/2 - oppure la combinazione di un agonista del Toll-Like Receptor 4 (TLR4a) o del Toll-Like Receptor 7 (TLR7a) con idrossido di alluminio – che polarizzano la risposta verso il profilo Th1. Gli adiuvanti sono stati valutati per la loro capacità di migliorare le risposte immunitarie contro il vaccino TdaP contenente tre antigeni di B. pertussis: tossina della pertosse geneticamente detossificata (PT-9K/129G), emoagglutinina filamentosa (FHA) e pertactina (69K).
La rapida induzione di titoli anticorpali e la polarizzazione della qualità della risposta immunitaria indotte dagli adiuvanti qui esaminati sostengono pienamente la potenzialità di sostituire i sali di alluminio con adiuvanti alternativi che migliorino l’immunogenicità di vaccini combinati contenenti aP.

Conclusioni:
Complessivamente, i risultati raccolti suggeriscono la possibilità di modulare la qualità e l'efficacia di un vaccino complesso lavorando sulla componente adiuvante. Migliorare la caratterizzazione analitica dei vaccini e indirizzare una polarizzazione razionale della risposta immunitaria sono proposte come strategie efficaci da perseguire per lo sviluppo dei vaccini combinati della prossima generazione.

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Tipo di EPrint:Tesi di dottorato
Relatore:Montecucco, Cesare
Correlatore:Baudner, C. Barbara
Dottorato (corsi e scuole):Ciclo 27 > scuole 27 > BIOSCIENZE E BIOTECNOLOGIE > BIOLOGIA CELLULARE
Data di deposito della tesi:30 Gennaio 2015
Anno di Pubblicazione:30 Gennaio 2015
Parole chiave (italiano / inglese):Formulazione di vaccini / Vaccine formulation Adiuvanti / Adjuvants Alluminio idrossido / Aluminum hydroxide Vaccini combinati / Combination vaccines Pertosse acellulare / Acellular pertussis
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/09 Farmaceutico tecnologico applicativo
Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:7838
Depositato il:12 Nov 2015 11:49
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