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Zurli, Vanessa (2016) Novel strategies to improve anti-influenza vaccines. Positive contribution of adjuvanted immunization strategies during aging and in the resolution of viral-bacterial co-infections. [Ph.D. thesis]

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Abstract (english)

Despite the extensive use of anti-influenza vaccines during the last decades, influenza and its complications are still a major cause of morbidity and mortality worldwide. Older adults (>65 years) are particularly susceptible to influenza illness and it is estimated that approximately 90% of influenza deaths occurs in this population. Notably secondary bacterial infections (SBI), the majority of which are associated with S. pneumoniae or S. aureus, make a significant contribution to deaths during influenza epidemics and pandemics, through a phenomenon known as “excess mortality”. In order to reduce influenza-driven mortality, broader protective vaccines are needed and different strategies are possible. Among these, universal influenza vaccines or even broad-spectrum “pneumonia” vaccines targeting a range of different viral and bacterial respiratory pathogens are thinkable. To allow the design of such vaccines, a multitude of basic questions - such as the ideal vaccine composition, appropriate vaccine adjuvants and an understanding of the complex pathogen interactions - have to be addressed.
With the current work we wanted to address this specific medical need. In the first part we studied the special immunological pre-requisites for successful influenza vaccination in the elderly, while in the second part we extended our focus on the impact of different influenza vaccines on viral-bacterial co-infection.
Elderly people are particularly susceptible to influenza infection and its complications, but respond poorly to conventional vaccines. MF59-adjuvanted influenza vaccines have been specifically developed and licensed to target this age population and are considered - together with similar formulations - as the best strategy to prevent influenza disease in the context of immunosenescence. Yet, the development process was entirely empirical and it is only poorly understood how MF59 contributes to successfully restoring responsiveness to influenza vaccines in the elderly.
To deeply investigate the mechanism of action of MF59 in elderly subjects, we assessed immune response elicited by this adjuvant in old mice (>18 months). Our results showed that MF59 is able to potentiate responses against influenza antigens not only in young mice (6-8 weeks), but also in older ones: it enhanced immune cell recruitment at the site of injection, antigen-translocation to draining lymph nodes, CD4+ T cell response and germinal center formation. Yet, in line with clinical data, we noticed that hemagglutination inhibition (HI) antibody titers induced by MF59-adjuvanted vaccine in old mice were similar to those obtained in young ones immunized with not adjuvanted antigens arguing for the fact that MF59 can overcome some but not all aspects of immunosenescence. Accordingly, we wanted to dissect, which of the MF59-induced signaling cascades were impacted by aging. We recently showed in young mice, that transient ATP-release in injected muscle is an important contributor to adjuvanticity of MF59. Here we verified that also in aged mice ATP plays a central role for adjuvant activity. Yet, while in young mice it is not the only actor of adjuvanticity, in elderly other MF59-targeted immune pathways seem to be reduced due to “immunosenescence” or “inflammaging”.
MF59 is a safe, effective and well established vaccine adjuvant for influenza vaccine in humans with millions of doses administered. Whether there is room for further improvement of anti-influenza responses especially in the vulnerable elderly population has to be assessed.
Complications from secondary bacterial infection are a leading cause of influenza-associated morbidity and mortality. Anti-influenza vaccination is considered the best strategy to counteract primary viral disease spread. Moreover data from animal models suggest that it is also an effective method to prevent subsequent secondary bacterial pneumonia. Yet, currently approved influenza vaccines are typically assessed only for their capacity to elicit neutralizing antibodies specific for the homologous (vaccine-type) influenza strain. Protection against heterotypic (antigenic shift by mutations within influenza strain) or against heterologous (HA and/ or NA differing from those in the vaccine strain) influenza infection is studied to a lesser extent. And importantly, studies in humans have typically not been designed or appropriately powered to assess effectiveness against SBI.
It can be assumed that prevention of influenza infection through vaccination would also prevent complications such as SBI, but in case of heterotypic or heterologous virus challenge - as would easily occur during a normal influenza season - does partial protection significantly affect bacterial super-infections? Furthermore different types of influenza vaccines induce differential innate and adaptive responses in infected individuals that might impact positively or negatively on SBI. Does this occur and can it be measured?
We aimed to answer these questions in pre-clinical models of differently anti-influenza immunized mice. To that extent, we vaccinated BALB/c mice systemically with an A/California/7/2009 (H1N1) subunit vaccine either as plain antigens or adjuvanted with i) MF59 to induce a mixed Th1/Th2 response, ii) a combination of MF59 and CpG to get a more Th1-prone response or with iii) LTK63 administered via the mucosal route to obtain a Th1/Th17 polarized response. After vaccination mice were challenged with the heterologous mouse adapted strain A/Puerto Rico/8/1934 (H1N1) (PR8) and infection course and various aspects of immune response were dissected. We found that vaccination via different administration routes and adjuvants enhances immune responses to influenza virus infection by creating in the host a differently Th-polarized environment: all tested priming conditions induced strong vaccine-specific Th1, Th2 or Th17-polarized responses and anti-influenza antibody titers that quickly restored pre-infection immune environment in lung. On the contrary, plain immunization was significantly less effective: mice showed high viral titers similar to those of naïve ones and had overall higher influx of immune cells into the lung, an indication of ongoing inflammation. Notably mucosal vaccination with LTK63, though inducing lower HI titers, was equally good in protecting mice from influenza infection as systemic vaccination with MF59±CpG, strongly arguing for an important contribution of additional immune responses to protection in the setting of heterologous infection.
Secondly we asked if different flavors of immune responses during influenza infection would have a beneficial or detrimental impact on SBI caused by Methicillin-resistant S. aureus (MRSA) USA300, which has been recently associated with increasing cases of fulminant post-influenza pneumonia in humans. To this end we set up a new influenza-bacterial co-infection model in previously anti-influenza vaccinated mice. Immunizations were performed as before to skew the immune response towards different Th profiles. Mice were then infected with influenza PR8 virus and six days later co-infected with S. aureus. In this co-infection model we followed disease evolution by measuring mouse weight loss and pathogen clearance in lungs.
In this setting the differences between the single vaccination strategies became even more evident. While non-adjuvanted vaccine protected significantly from single influenza infection, it conferred little protection from viral-bacterial co-infection. Plain vaccinated mice were subjected to severe bacterial overgrowth and to high morbidity and mortality during SBI similarly to naïve mice. They just differed from naïve mice by their capability to control virus loads during SBI, while naïve mice showed a second wave of lung viral titer increase after bacterial infection that is a typical consequence of SBI. In contrast, we demonstrated that all adjuvanted vaccines were superior in preventing not only viral infection but also bacterial superinfection as compared to plain antigens vaccination. In particular Th1-prone mice efficiently controlled influenza infection better than those receiving other formulations and were nearly not affected by SBI.
Altogether our results showed that adjuvanted-influenza vaccines are an efficient method to counteract not only heterologous influenza infection, but also eventual SBI. Moreover we demonstrated that the adjuvant MF59 is extremely important to enhance immunity against virus antigens in aged preclinical models. MF59 could eventually be improved by adding immunopotentiators like CpG to further enhance Th1-prone immune responses. These responses seem to be superior for preventing both viral and viral-bacterial infection.

Abstract (italian)

Nonostante che negli scorsi decenni si sia fatto un ampio uso dei vaccini anti-influenzali, l’influenza e le relative complicazioni sono tuttora tra le maggiori cause mondiali di morbilità e mortalità. Le persone più anziane (>65 anni di età) sono particolarmente sensibili all’influenza e si stima che all’interno di tale popolazione si ritrovi circa il 90% delle morti dovute alla malattia. Le infezioni batteriche secondarie (SBI) causate principalmente da S. pneumoniae e S. aureus rappresentano un’importante causa di morte durante le epidemie e pandemie influenzali attraverso un fenomeno conosciuto come “mortalità eccessiva”. Affinché si riesca a ridurre la mortalità dovuta all’influenza, occorrono vaccini con un più ampio spettro di protezione. Tra le possibili strategie troviamo vaccini influenzali universali o addirittura vaccini “generici” contro la polmonite in grado di difendere l’organismo da un’ampia gamma di virus e batteri patogeni per l’apparato respiratorio. Affinché si arrivi allo sviluppo di tali vaccini innovativi, occorre definire innanzitutto alcuni aspetti basilari, quali ad esempio la loro composizione ideale e la scelta degli adiuvanti appropriati, il tutto insieme ad una maggiore conoscenza delle complesse interazioni tra i patogeni target.
Nel presente lavoro di tesi abbiamo voluto approfondire questo specifico aspetto medico. Nella prima parte dello studio abbiamo definito quali sono i particolari prerequisiti immunologici per la buona riuscita della vaccinazione anti-influenzale negli anziani. Nella seconda parte invece ci siamo focalizzati sull’impatto che differenti tipologie di vaccini anti-influenzali possono avere sulla co-infezione tra il virus e un batterio.
La popolazione anziana, che è particolarmente suscettibile all’influenza e alle sue complicazioni, risponde scarsamente ai vaccini convenzionali. I vaccini adiuvantati con MF59 sono stati sviluppati e approvati specificatamente per questa popolazione target e, insieme a formulazioni simili, sono considerati ad oggi la migliore strategia per prevenire l’influenza nell’ambito dell’immunosenescenza. Tuttavia lo sviluppo di tali vaccini è stato puramente empirico e ben poco si sa di come MF59 contribuisca a ristabilire nelle persone anziane un’efficiente risposta al vaccino.
In questo studio abbiamo analizzato la risposta immunitaria indotta da MF59 in topi anziani (>18 mesi) in modo da definire meglio il meccanismo di azione dell’adiuvante nei soggetti in età avanzata. Dai nostri risultati si evince che MF59 è in grado di potenziare la risposta immunitaria nei confronti dell’influenza non solo nei topi giovani (6-8 settimane), ma anche in quelli più vecchi. Abbiamo dimostrato infatti che l’adiuvante induce robusto reclutamento di cellule immunitarie al sito d’iniezione del vaccino, potenzia la traslocazione dell’antigene ai linfonodi drenanti e incrementa la risposta delle cellule T CD4+ e la formazione dei centri germinativi. Tuttavia, in linea con i risultati clinici, i titoli anticorpali d’inibizione dell’emoagglutinazione (HI) indotti dalla vaccinazione con MF59 nei topi anziani raggiungono livelli simili a quelli ottenuti nei topi più giovani vaccinati senza l’adiuvante. Da questo risultato possiamo dedurre che MF59 è in grado di porre rimedio ad alcuni degli aspetti caratterizzanti l’immunosenescenza, ma non a tutti. In accordo con ciò, abbiamo voluto definire meglio quali tra le cascate di segnalazione indotte da MF59 è impattata dall’invecchiamento. In nostro gruppo ha recentemente dimostrato in topi giovani che l’iniezione di MF59 nel muscolo induce un rilascio transiente di ATP che si rivela poi importante per l’effetto adiuvante del prodotto. In questo lavoro di tesi abbiamo verificato che anche nei topi anziani il rilascio di ATP gioca un ruolo centrale per l’attività dell’adiuvante. Tuttavia, mentre nei topi più giovani tale rilascio non è l’unico “attore” del potenziamento immunologico indotto dall’adiuvante, in quelli più vecchi gli altri pathway avviati da MF59 sembrano essere impattati negativamente dall’immunosenescenza e dallo stato di continua infiammazione tipico degli anziani.
MF59 è un adiuvante sicuro ed efficace e il suo utilizzo nella vaccinazione anti-influenzale umana è ormai consolidato con milioni di dosi somministrate. Quello che resta da definire è se c’è la possibilità di un ulteriore miglioramento della risposta anti-influenzale soprattutto in una popolazione così vulnerabile come quella degli anziani.
Le cause principali di morbilità e mortalità associate con l’influenza sono da imputarsi alle SBI. La vaccinazione anti-influenzale è considerata ad oggi la migliore strategia per combattere la diffusione della malattia. Inoltre, dati risultanti da studi su modelli animali, rivelano che la vaccinazione anti-influenzale è anche un metodo efficace nella prevenzione di polmoniti batteriche conseguenti all’influenza. Purtroppo i vaccini attualmente in commercio sono testati soltanto per la loro capacità di indurre anticorpi neutralizzanti specifici per il virus influenzale omologo al ceppo contenuto nel vaccino stesso. Non sono molto diffusi studi riguardanti la protezione indotta dai vaccini nei casi d’infezioni di virus influenzali eterosubtipici (cioè varianti antigeniche dovute a mutazioni all’interno di un ceppo influenzale) o eterologhi (le cui proteine HA e/ o NA differiscono da quelle presenti nel vaccino). Inoltre occorre notare che non sono stati ancora stabiliti studi clinici appropriati per definire l’effettiva efficienza dei vaccini influenzali nei confronti delle SBI.
Si può facilmente assumere che la prevenzione dell’infezione influenzale indotta dalla vaccinazione possa anche prevenire le relative complicazioni come le SBI, ma in caso d’infezione di virus eterosubtipici o eterologhi - situazione che può normalmente verificarsi durante la stagione influenzale – quale impatto può avere una protezione parziale dall’influenza sulle superinfezioni batteriche? Inoltre formulazioni diverse dei vaccini anti-influenzali inducono negli individui infettati risposte immunitarie innate e adattative diverse che possono avere un impatto positivo o negativo sulle SBI. Questa situazione si verifica realmente e come può essere quantificata?
In questo lavoro ci siamo fissati l’obiettivo di rispondere a queste domande utilizzando come modello di studio pre-clinico topi immunizzati contro l’influenza mediante svariate formulazioni di vaccini. Brevemente i topi BALB/c sono stati vaccinati per via sistemica con il vaccino a subunità specifico per il virus A/California/7/2009 (H1N1) sia utilizzando gli antigeni influenzali da soli, sia in formulazioni adiuvantate con i) MF59 in modo da indurre una risposta mista Th1/Th2, ii) MF59+CpG per ottenere una risposta polarizzata verso il profilo Th1 o con iii) LTK63 somministrato per via mucosale affinché la risposta immunitaria fosse indirizzata verso un profilo Th1/Th17. Dopo la vaccinazione, i topi sono stati infettati col virus A/Puerto Rico/8/1934 (H1N1) (PR8): tale virus è eterologo rispetto agli antigeni contenuti nel vaccino utilizzato ed è un ceppo virale adattato al topo. Nel corso dello studio abbiamo seguito l’evoluzione dell’infezione e vari aspetti della risposta immunitaria. I nostri risultati dimostrano che la somministrazione del vaccino mediante vie diverse e l’utilizzo di svariati adiuvanti potenziano la risposta immunitaria nei confronti dell’infezione influenzale creando nell’ospite un ambiente polarizzato verso i diversi profili Th: tutte le condizioni d’immunizzazione testate inducono elevate risposte immunitarie polarizzate verso i profili Th1, Th2 o Th17 e titoli anticorpali in grado di ristabilire velocemente la situazione immunitaria del polmone ad un livello pari a quello presente prima dell’infezione. Al contrario, il vaccino non adiuvantato si è dimostrato significativamente meno efficiente: i topi mostrano elevati titoli virali simili a quelli dei topi naïve ed hanno un robusto influsso di cellule immunitarie all’interno dei polmoni che identifica l’instaurazione di un processo infiammatorio. Occorre notare che la vaccinazione mucosale adiuvantata con LTK63, pur inducendo titoli HI più bassi, stabilisce un livello di protezione dall’infezione pari a quello della vaccinazione sistemica con MF59±CpG. Questo ci fa supporre che nel contesto di un’infezione eterologa, ai fini della protezione, sia molto importante il contributo di risposte immunitarie addizionali alla risposta anticorpale sistemica.
Partendo dai risultati ottenuti, ci siamo chiesti se le varie tipologie di risposta immunitaria indotte durante l’infezione d’influenza avessero un impatto positivo o negativo su SBI causate da S. aureus USA300 resistente alla meticillina (MRSA). Questo ceppo batterico è stato infatti recentemente associato con un numero crescente di casi di polmonite fulminante post-influenzale. A questo scopo abbiamo stabilito un nuovo modello d’infezione influenzale-batterica nei topi vaccinati per l’influenza. Le immunizzazioni sono state eseguite come in precedenza in modo da polarizzare le risposte immunitarie verso i vari profili Th. In seguito i topi sono stati infettati col virus influenzale PR8 e sei giorni dopo co-infettati con S. aureus. In questo modello di co-infezione abbiamo seguito l’evolversi della malattia misurando il peso corporeo dei topi e quantificando la replicazione dei patogeni nei polmoni.
Nel nostro modello di co-infezione le differenze tra le singole strategie di vaccinazione si sono marcate ancora di più. Sebbene il vaccino non adiuvantato proteggesse abbastanza bene dalla semplice infezione influenzale, è in grado di conferire soltanto una protezione parziale durante la co-infezione. Infatti, i topi vaccinati con tale formulazione sono soggetti a un’incontrollata crescita batterica e mostrano elevati livelli di morbilità e mortalità comparabili a quelli dei topi naïve. Si discostano dai topi naïve soltanto per la loro capacità di controllare la replicazione virale durante la SBI: mentre i topi naïve mostrano una seconda ondata d’incremento del titolo virale nei polmoni dopo l’infezione batterica - tipica conseguenza della SBI -, i topi che avevano ricevuto il vaccino non adiuvantato continuano il controllo del virus indipendentemente dalla SBI. Comparando i risultati del vaccino non adiuvantato con quelli ottenuti dalle tre formulazioni contenenti adiuvanti, abbiamo dimostrato che tutti i vaccini adiuvantati sono superiori non solo nella prevenzione dell’influenza, ma anche nel caso della superinfezione batterica. In particolare i topi il cui sistema immunitario aveva una polarizzazione verso il profilo Th1 sono in grado di controllare più efficientemente l’infezione influenzale rispetto ai topi che avevano ricevuto una delle altre due formulazioni adiuvantate e inoltre la SBI non ha quasi impatto negativo su di loro.
Nel complesso i nostri risultati dimostrano che i vaccini influenzali adiuvantati sono un metodo efficiente per combattere non solo un’infezione influenzale eterologa, ma anche un’eventuale SBI. Abbiamo inoltre dimostrato che l’adiuvante MF59 è di estrema importanza per potenziare la risposta immunitaria nei confronti degli antigeni virali nel modello pre-clinico di topi anziani. MF59 può essere eventualmente implementato mediante l’aggiunta di “potenziatori” del sistema immunitario come ad esempio il CpG, in modo da rafforzare le risposte polarizzate verso il profilo Th1. Queste risposte, infatti, risultano essere superiori per la prevenzione sia della semplice infezione virale sia della co-infezione.

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EPrint type:Ph.D. thesis
Tutor:Montecucco, Cesare
Supervisor:Seubert, Anja
Data di deposito della tesi:14 January 2016
Anno di Pubblicazione:14 January 2016
Key Words:influenza / influenza, elderly / anziani, vaccine adjuvants / adiuvanti per vaccini, S. aureus / S. aureus, co-infection / co-infezione
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:9036
Depositato il:06 Oct 2016 15:27
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