Dissertations / Theses on the topic 'SARS-CoV-2 Vaccine'

Bakgrund: I slutet av 2019 upptäcktes flertalet fall av pneumoni av okänd etiologi i Wuhan, Kina. Efter isolering och sekvensering framkom det att det rörde sig om ett coronavirus, benämnt SARS-CoV-2. Sociala restriktioner och munskydd har inte lyckats stoppa denna pandemi, och hoppet ligger nu på de olika vaccinkandidater som började utvecklas under 2020. Syfte: Syftet var att jämföra olika vaccins effektivitet och förekomst av olika biverkningar. Metod: En systemisk litteraturstudie utfördes, där en sökning i Pubmed utfördes och fyra artiklar valdes ut till arbetet för att jämföra vaccineffektivitet och biverkningar för de tre vaccin som var godkända av läkemedelsverket i februari. Resultat: Pfizer/BioNTechs mRNA-vaccin hade en effektivitet på 94,8%, Modernas mRNA-vaccin en effektivitet på 94,1% och Oxford-AstraZenecas vektorvaccin uppvisade en effektivitet på 70,4%. De vanligaste biverkningarna vid vaccinering var smärta vid injektionsplatsen, huvudvärk samt utmattning. Slutsats: En tillfredsställande jämförelse kunde inte genomföras då de olika fas III studierna utfördes på olika åldersgrupper och i olika delar av världen där SARS-CoV-2 mutationerna skiljde sig åt, vilket kan ha påverkat resultaten.<br>Background: At the end of 2019, several cases of pneumonia of unknown ethology were discovered in Wuhan, China. After isolating and sequencing the pathogen it became apparent that it was a Coronavirus, named SARS-CoV-2. Social restrictions and mask wearing mandates have not managed to stop this pandemic, and the hope lies with the different vaccine candidates that started to be developed during 2020. Aim: The aim was to compare different vaccines efficacy and prevalence of side effects. Method: A systemic literature study was implemented, the search was done in Pubmed and four papers were selected to compare vaccine efficacy and side effects for the three vaccines that were approved by Läkemedelsverket in February. Results: Pfizer/BioNTech’s mRNA-vaccine showed an efficacy of 94,8%, Moderna’s an efficacy of 94,1% and Oxford-AstraZeneca’s vector vaccine showed an efficacy of 70,4%. The most common side effects following vaccination was pain at the site of injection, headache and fatigue. Conclusion: A satisfying comparison could not be achieved since the different phase III studies were performed on different age groups and in different parts of the world where SARS-CoV-2 mutations differ, which could impact the results.

Introduktion: Coronavirus är RNA-virus med ett lipidhölje som är täckt utav karaktäristiska spikprotein. De mest kända coronavirusvarianterna är SARS-CoV-1 som var aktiv mellan 2002-2004, MERS-CoV som har varit aktiv sedan 2012 och SARS-CoV-2 som har varit aktiv sedan 2019–tillsvidare. SARS-CoV-2 infektionen betecknades januari 30 2020 som en pandemi. Flera läkemedelsföretag har forcerat ??? till att framställa vaccin riktad mot SARS-CoV-2, “The United States Food and Drug Administration” (FDA) och “European Medicines Agency” (EMA) har nödgats att ge ut “Emergency Use Authorization (EUA) i hopp om att få kontroll på dess spridining. Syfte och mål: Syftet med arbetet är att undersöka säkerheten och effektiviteten hos de EMA-godkända vaccinerna riktade mot SARS-CoV-2. Metod: Studierna för vardera vaccin hittades och valdes ut genom World Health Organizations (WHO) “Draft landscape and tracker of COVID-19 candidate vaccines”. Totalt inkluderades åtta studier baserade på tio kliniska prövningar som undersökte säkerheten och effektiviteten hos de fyra ledande vaccinerna från Pfizer BioNTech, Moderna, AstraZeneca och Johnson &amp; Johnson. Resultat: De fyra undersökta vaccinerna visade en god säkerhet utan grövre biverkningar. De vanligaste biverkningarna hos samtliga vaccin var lokal smärta, trötthet och huvudverk. Dessa biverkningar varade mellan en till två dagar efter vaccination och var till större del milda. Större skillnader kunde ses hos de olika vaccinernas effektivitet, Pfizer BioNTech och Modernas mRNA-vacciner visade på effektiviteter runt 95% medan AstraZeneca och Johnson &amp; Johnsons adenovirus-vektor-vacciner visade på effektiviteter runt 66-70%. Diskussion: Inga större skillnader i säkerhet kunde ses mellan de undersökta vaccinerna. AstraZeneca använde ett influensa vaccin istället för isoton vattenlösning till deras kontrollgrupper. Detta kan ha haft en påverkan på placebo och resultaten från deras prövningar. En tydlig skillnad i effektivitet kunde ses mellan de olika vaccintyperna, vilket har ett stort inflytande på hur lätt man kan inducera flockimmunitet hos en befolkning. Eftersom flockimmunitet har en stor roll i både att bromsa spridningen men även i att förebygga förekomsten av nya virus varianter så bör endast mRNA vacciner rekomenderas om möjligt.<br>Introduction: Coronaviruses are RNA viruses with a lipid envelope that is covered by characteristic spike protein. The most well-known coronaviruses are SARS-CoV-1 which were active between 2002-2004, MERS-CoV which is active since 2012 and SARS-CoV-2 which is active since 2019. SARS-CoV-2 was designated a pandemic January 30, 2020. Several pharmaceutical companies have been rushing to produce vaccines targeting SARS-CoV-2, The United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have had to issue Emergency Use Authorization (EUA) in the hope of gaining control of its spread. Objective: The purpose of this study is to investigate the safety and efficacy of the EMA-approved vaccines targeting SARS-CoV-2. Method: The studies for each vaccine were found and selected through the World Health Organizations' (WHO) "Draft landscape and tracker of COVID-19 candidate vaccines". A total of eight studies were included based on ten clinical trials examining the safety and efficacy of the four leading vaccines from Pfizer BioNTech, Moderna, AstraZeneca and Johnson &amp; Johnson. Results: The four vaccines examined showed good safety without any serious side effects, the most common side effects with all vaccines were local pain, fatigue, and headache. These side effects lasted between one to two days after vaccination and were mostly mild. Larger differences could be seen in the efficacy of the different vaccines, with Pfizer BioNTech and Moderna's mRNA vaccines showing efficacies of around 95%. While AstraZeneca and Johnson &amp; Johnson's adenovirus vector vaccines showed efficacies of around 66-70%. Discussion: No major differences in safety could be seen between the vaccines examined. AstraZeneca used an influenza vaccine instead of isotonic aqueous solution for their control groups, this may have had an impact on placebo and thus the results of their trials. A clear difference in efficacy could be seen between the different types of vaccines. This has a great influence on how easily one could induce herd immunity to a population. Herd immunity plays a major role in both slowing the spread but also in preventing the occurrence of new virus variants, therefore mRNA vaccines should be recommended if possible.

In questo lavoro di tesi è stata valutata la risposta immunitaria umorale e cellulo-mediata, in seguito alla somministrazione del vaccino a mRNA anti-COVID-19 (Pfizer mRNA BNT162b2), in pazienti trattati con farmaci immunosoppressi e con immunodeficienza comune variabile (CVID). Dall’Unità di Reumatologia e Immunologia Clinica, dell’A.O. Spedali Civili di Brescia sono stati reclutati 38 pazienti, di cui 34 affetti da malattie reumatiche croniche (RDs), 4 da CVID e 11 persone sane (HC), utilizzate come controlli. Tutti i pazienti con RDs erano sottoposti ad una terapia a base di corticosteroidi e/o trattamento immunosoppressivo e/o farmaci biologici; in particolare, 14 pazienti assumevano abatacept (ABA), 10 rituximab e 10 tocilizumab. In primo luogo, è stato valutato il titolo anticorpale sia contro la proteina del nucleocapside (N) che della proteina Spike (S) di SARS-CoV-2 mediante immunodosaggio ad elettro chemiluminescenza. È stata analizzata la risposta immunitaria cellulo-mediata dei linfociti T CD4+ e CD4+-CD8+ mediante il test di rilascio dell’interferone- (IFN-) e valutata la produzione di chemochine indotte dall’IFN- (CXCL9 e CXCL10) e dalle cellule dell’immunità innata (CCL2, CXCL8 e CCL5), mediante l’uso di cytometric bead array method (CBA) a seguito di stimolazione con due pool di peptidi differenti della proteina S di SARS-CoV-2. Infine, mediante citofluorimetria, è stata studiata l’espressione di marcatori di attivazione precoce, come CD40L, CD137 e di citochine intracellulari, come IL-2, IFN- e IL-17, a seguito di stimolazione dei linfociti T con due pool di peptidi differenti della proteina S. I principali risultati ottenuti sono stati: (i) una ridotta risposta anti-S nei pazienti trattati con ABA, ripristinata però dopo la terza dose vaccinale; (ii) una ridotta attivazione delle cellule T dovuta ad una riduzione di IFN- e chemochine (CXCL9 e CXCL10); (iii) una riduzione di cellule T CD8+ della memoria nei pazienti trattati con ABA; (iv) una significativa abilità dei pazienti trattati con ABA di sviluppare una risposta cellulo-mediata delle cellule T CD4+, se stimolate con antigeni derivati dalla proteina S di SARS-CoV-2. Nonostante questo lavoro sia stato limitato dal basso numero di pazienti reclutati, l’esecuzione di numerose valutazioni effettuate a livello cellulare, ha contribuito a dimostrare il tipo di risposta immunitaria che i pazienti sottoposti a diverse terapie immunosoppressive sono stati in grado di generare a seguito della vaccinazione anti-COVID-19. La capacità di generare cloni di linfociti T CD4+ SARS-CoV-2 specifici in seguito alla vaccinazione, ha garantito a questi pazienti un’efficace protezione contro il virus. Inoltre, dal momento che, i pazienti trattati con ABA, dopo la somministrazione della terza dose di vaccino a mRNA anti-COVID-19 hanno acquisito la capacità di aumentare la risposta anticorpale, si può affermare che dosi ripetute di vaccino potrebbero essere necessarie al fine di ottimizzare la risposta immunologica in pazienti altamente vulnerabili.<br>In this study, we analyzed T cell-mediated response after COVID-19 mRNA vaccine in immunosuppressed patients and patients with common variable immunodeficiency disease (CVID). We enrolled 38 patients, from the Unit of Rheumatology and Clinical Immunology, of the A.O. Spedali Civili of Brescia, Italy, and 11 healthy sex- and age- matched controls (HC). Four patients were affected by CVID and 34 by chronic rheumatic diseases (RDs). All patients with RDs were treated by corticosteroid therapy and/or immunosuppressive treatment and/or biological drugs: 14 patients were treated with abatacept, 10 with rituximab and 10 with tocilizumab. Total antibody titer to SARS-CoV-2 spike protein was assessed by electrochemiluminescence immunoassay, CD4+ and CD4+-CD8+ T cell-mediated immune response was analyzed by interferon- (IFN-) release assay, the production of IFN-γ-inducible (CXCL9 and CXCL10) and innate-immunity chemokines (CCL2, CXCL8 and CCL5) by cytometric bead array after stimulation with different spike peptides. The expression of CD40L, CD137, IL-2, IFN-γ and IL-17 on CD4 and CD8 T cells, evaluating their activation status, after SARS-CoV-2 spike peptides stimulation, was analyzed by intracellular flow cytometry staining. The main findings were (i) a reduced anti-S response in ABA-treated group, restored after the third dose of vaccine; (ii) an impaired T cell activation, represented by a reduction of IFN-γ and related chemokines; (iii) a reduction of effector memory CD8+ T cells in ABA-treated group; (iiii) a significant ability of ABA treated group to mount a CD4 T cell response, when stimulated with spike derived antigens. Our work was limited by the low number of patients enrolled but performing extended cellular assessments, contributed to explain which kind of immune response patients chronically exposed to different immunosuppressive regimen are able to generate in response to COVID-19 vaccination. The preserved ability to generate clones of CD4+ T lymphocytes specific for SARS-CoV-2 spike proteins represents the assurance of an effective protection of vaccination to SARS-CoV-2. Moreover, after the third dose of COVID-19 mRNA vaccine, ABA-treated patients acquired the capability to produce a strong antibody response, despite they maintained a significant reduction of CD8+ T response. All these data represent a critical message from laboratory research bench to clinical patients’ side, suggesting that repeated vaccine doses may be necessary to optimize the immunological response and to induce more robust serological responses in these high-risk vulnerable patients.

La pandémie de COVID-19, causée par le SRAS-CoV-2, a entrainé une morbidité et une mortalité importantes, mettant à rude épreuve les systèmes de santé mondiaux. Les vaccinations et les interventions non pharmaceutiques (INP) sont essentielles pour contrôler la propagation du virus. Avant les vaccins, les gouvernements s’appuyaient sur des INP dont l’impact épidémiologique et sociétal restait incertain, notamment sur plusieurs vagues pandémiques. Le déploiement des vaccins a augmenté l’immunité collective, mais l’émergence de variants préoccupants (VoCs) échappant à l’immunité et l’affaiblissement de l’immunité induite ont réduit l’immunité effective. La dynamique à long terme de ce déclin est mal comprise, surtout dans le contexte d’infections multiples et par divers VoCs. Les épidémies étant partiellement observées et leur dynamique non linéaire, les modèles mathématiques sont bien adaptés pour leur analyse. Dans ma thèse, j’ai appliqué ces modèles à diverses données COVID-19, depuis les données agrégées sur les infections et les hospitalisations jusqu’aux titres d’anticorps (Ac) chez les individus, pour quantifier l’efficacité des INP et vaccins, identifier les seuils de protection des Ac et caractériser la décroissance de l’immunité. Mon premier objectif était d’estimer l’efficacité des INP et des vaccins en France et d’explorer des scénarios contrefactuels des INP et des vaccins. Nous avons développé un modèle mécaniste ajusté aux données épidémiologiques françaises de mars 2020 à octobre 2021. Le modèle a montré une réduction significative de la transmission virale grâce aux INP, bien que leur efficacité ait diminué avec le temps. Les simulations ont montré que les vaccins avaient sauvé près de 160000 vies au cours de la période étudiée, mais qu’une mise en œuvre plus précoce ou un déploiement plus rapide aurait évité encore plus de décès. Pour comprendre la variabilité des estimations de l’efficacité des INP, nous avons évalué deux méthodologies pour mon deuxième objectif : les modèles mécanistes et une régression en deux étapes couramment utilisée, qui d’abord estime le nombre de reproduction ( Rt), puis le régresse sur les paramètres des INP. En utilisant des données simulées, les modèles mécanistes ont montré un biais minimal (0-5%) et une couverture d’intervalle de confiance (IC) élevée, tandis que les régressions en deux étapes ont montré des biais jusqu’à 20% et une couverture d’IC inferieure. Ce biais était dû à la déplétion des susceptibles et aux difficultés d’estimation de Rt, montrant que cette méthode nécessite prudence malgré sa rapidité. Les modèles épidémiologiques précis nécessitent des paramètres actualisés. Mon troisième objectif était donc 1) relier les niveaux d’Ac SARS-CoV-2 au risque de (ré)infection et 2) caractériser la décroissance des Ac. Grâce aux données d’Ac de plus de 220000 donneurs de sang canadiens entre avril 2020 et décembre 2023, nous avons constaté que les Ac anti-S et anti-N réduisaient le risque d’infection, avec un effet plus prononcé des anti-N à de faibles titres. J’ai estimé avec des modèles de décroissance biphasique que 51.3% (95% IC 40.6-66.1%) des individus tomberaient en dessous des niveaux détectables d’Ac anti-N dans les trois ans suivant une infection. La durée de détection des Ac augmentait après chaque infection. Cependant, les Ac chutaient en quelques mois en dessous des seuils requis pour une protection substantielle, même après plusieurs infections et vaccinations, indiquant la nécessité d’administrer des rappels réguliers pour maintenir la protection. Les analyses dans ma thèse soulignent l’importance des interventions rapides et du suivi continu de l’immunité pour mieux se préparer aux futures épidémies. De plus, j’ai démontré que les modèles mathématiques sont un outil puissant pour orienter la prise de décision en santé publique et les stratégies de prévention<br>The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant morbidity and mortality, straining healthcare systems worldwide. Fundamental approaches for controlling viral spread and mitigating its impact are vaccinations and non-pharmaceutical interventions (NPIs). Before vaccines became available, governments relied on NPIs with largely unknown epidemiological and societal impacts. Despite numerous studies, the effectiveness of NPIs on COVID-19 dynamics remained uncertain, especially over multiple pandemic waves. With a gradual roll-out of vaccines, population immunity increased, but this increase in was counteracted by the emergence of immune-escaping variants of concern (VoCs) and waning of both infection- and vaccine-induced immunity. The long-term dynamics of this decline are currently not well characterized, particularly in the context of multiple infections and infections with different VoCs. Given the only partially observed nature of epidemics and their non-linear dynamics, mathematical models are uniquely suited for their analysis. In my thesis, I applied mathematical models to various COVID-19 data, from aggregated population-level data of infections and hospitalizations to antibody (Ab) titers in individuals, with the goal of quantifying the effectiveness of NPIs and vaccines, identifying protective Ab thresholds, and characterizing immunity waning dynamics. Specifically, my first objective was to estimate the effectiveness of NPIs and vaccines in France and explore counterfactual NPI and vaccine implementation scenarios. We developed a population-based mechanistic model, which we fit to epidemiological data in France from March 2020 to October 2021. The model showed a significant reduction in viral transmission by lockdowns, school closures, and curfews, though their effectiveness decreased over time. Simulations demonstrated that vaccines had saved nearly 160k lives over the study period, but an earlier implementation or a faster rollout could have prevented even more deaths. To understand why NPI effectiveness estimates vary across studies, we evaluated two methodologies in my second objective: mechanistic models and a commonly used two-step regression approach. The latter first estimates the reproductive number (Rt) and then regresses it against NPI parameters. Using simulated data of varying complexity, mechanistic models consistently showed minimal bias (0-5%) and high confidence interval (CI) coverage, whereas the two-step regressions had biases up to 20% and much lower CI coverage. The bias stemmed from the depletion of susceptibles and challenges in estimating Rt, indicating that caution is warranted with this method despite its simplicity and speed. Accurate epidemiological models require up-to-date parameters. My third objective was therefore two-fold: 1) to relate SARS-CoV-2 specific Ab levels to the risk of infection and 2) to characterize antibody waning. Using Ab data from over 220k Canadian blood donors between April 2020 and December 2023, we found that both anti-S and anti-N Abs reduced infection risk, with anti-N showing a stronger effect at lower titers. We used biphasic decay models to characterize waning dynamics and estimated that that 51.3% (95% CI 40.6-66.1%) of individuals would drop below detectable anti-N Ab levels within three years after a single infection. The duration of Ab detection increased after subsequent infections. However, antibodies waned within months below thresholds needed to attain substantial protection, even after multiple infections and vaccinations, indicating that continuous vaccine booster doses might be needed to sustain protection. The analyses I conducted in my PhD research highlight the importance of timely interventions and continuous monitoring of immunity to better prepare for future outbreaks. Moreover, I illustrated that mathematical models are a powerful tool to inform public health decision making and strategies

Ci troviamo in un singolare momento storico dovuto alla pandemia. In tutto il mondo si sono prodotti enormi cambiamenti della vita quotidiana, sono stati, e continuano ad essere, presi provvedimenti restrittivi al riguardo. Quest’emergenza sanitaria internazionale è qualcosa di nuovo, e nonostante gli studi sul SARS-CoV-2 siano moltissimi, le domande rimangono tante e altrettanti sono i dettagli che ancora non si sanno. In Germania il Robert Koch Institut è l’ente di riferimento per la situazione sanitaria, e attraverso il Covid è diventato ancora più importante. La voglia di rendere accessibile la pagina web anche al pubblico italiano mi ha spinto a scegliere il sito web del Robert Koch Institut come oggetto della mia tesina. In seguito, propongo degli approfondimenti sui compiti del RKI e il suo ruolo in Germania, facendone un confronto con l’Italia. Successivamente entro nello specifico del lavoro di traduzione con un’analisi dei tipi di testi, esponendo poi le varie proposte di traduzione per la Home della pagina web, per parti di altre sezioni di approfondimento sul SARS-CoV-19 e per le strategie da adottare per limitarne il contagio. Infine, il focus verte sulle difficoltà riscontrate nel tradurre. Per ultimo la bibliografia e in allegato la grafica originale delle schermate del sito web che sono state tradotte.

Human Immunodeficiency Virus (HIV-1) is the aetiologic agent of AIDS. Presently there are ~38 million HIV-1 infected individuals worldwide and ~1 million deaths in 2019. Since its discovery, the quest for vaccine candidate for HIV-1 is alive, yet no effective vaccine exists till date. HIV-1 viral displayed Envelope (Env) protein is the primary viral target of the humoral immune system and is thus an obvious vaccine candidate. The historic RV144 HIV-1 clinical trial resulted in a modest efficacy of the gp120 clade B/E vaccine candidate and renewed hope in finding a HIV-1 vaccine. However, monomeric gp120 does not induce protective antibodies and native-like trimeric Env was hypothesized to be a better candidate to induce broadly neutralizing antibodies. The recent structure of the BG505SOSIP.664 gp140 ectodomain reinvigorated interest in rational immunogen design. Chapter 1 outlines the HIV-1 virus, organisation, and structures of the Env ectodomain gp140, gp120, gp41 and various strategies to elicit neutralizing antibodies. Chapter 2 provides proof of principle of a method involving a computational sequence and structure guided Rosetta mutational scanning approach PROSS, to generate high yielding variants of the Env derivative gp140 without altering the trimeric structure and antigenicity. Chapter 3 utilizes the approach of cyclic permutation to rationally design trimeric gp120 derivatives that display a native V1V2 apex and retain binding to quaternary epitope directed bNAbs such as PGT145 and PGDM1400. Further, a nanoparticle display of the cyclic permutant was carried out to improve the immunogenicity of these potentially attractive vaccine candidates. Chapter 4 utilizes a structure guided approach to derive stable Env ectodomain variants by a cyclic permutation design strategy and describes an approach to engineer disulfides at the trimer Apex to covalently link the trimers for obtaining dynamically stable Env variants. HIV-1 Env displays conserved epitopes that are targeted by broadly neutralizing antibodies. CD4 binding site (CD4bs) antibodies are amongst the most potent. These CD4bs in humans are observed to be produced from a highly restricted set of germline sequences of the antibody repertoire. Chapter 5 attempts to utilize a structure guided approach to computationally design antibodies derived from novel germlines that are predicted to be energetically stable. Functional and biochemical characterization of these antibodies is reported Chapter 5. With the ongoing COVID-19 pandemic we attempted to develop a vaccine candidate utilizing a structure guided approach in Chapter 6. The Receptor binding domain (RBD) of the Spike protein of SARS-CoV-2 has been observed to be the primary target of the most potent neutralizing antibodies. Hence in Chapter 6 we designed an RBD subunit vaccine candidate to combat COVID-19. The designed RBD derivative is highly thermotolerant and also immunogenic and produces neutralizing antibodies comparable to several candidates currently being tested in the clinic.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina<br>ABSTRACT:Introdução:Desde que o vírus da Síndrome Respiratória Aguda Grave (SARS-CoV-2) surgiu na China no final de 2019, infectou mais de 93 milhões de humanos em todo o mundo, sobrecarregando os sistemas de saúde e causando mais de 2 milhões de mortes. A fácil propagação do vírus e a necessidade de proteção dos profissionais de saúde chamaram a atenção para a vacina Bacillus Calmette-Guérin (BCG). O BCG é conhecido por efeitos não específicos na melhoria da imunidade inata. Algumas estudos sugeriram eventual proteção contra o coronavírus em nações onde o BCG faz parte da política nacional de vacinação.Métodos:Após o registro do protocolo no PROSPERO (ID = CRD42020188486), realizamos uma revisão sistemática da literatura nos bancos de dados PubMed, EMBASE, Web of Science, Clinical Trials.gov e Cochrane Library sobre o uso da vacina BCG para imunoprofilaxia de SARS-CoV-2. Uma pesquisa adicional foi realizada no MedRxiv para pre-prints. A seleção dos manuscritos foi realizada de acordo com as diretrizes PRISMA. O papel da vacinação BCG foi avaliado em termos de incidência e gravidade da doença COVID-19.Resultados:453 resumos foram inicialmente revistos ​​e recuperados 76 artigos com texto completo. Destes, 51 estudos preencheram os critérios de inclusão: 36 artigos originais e 15 ensaios clínicos.Verificou-se efeito positivo da vacina BCG na diminuição dos casos de COVID-19 e na mortalidade por COVID-19. Os indivíduos vacinados com BCG são menos propensos a contrair a doença do que os não vacinados, geralmente são assintomáticos e têm menor probabilidade de serem hospitalizados durante o curso da doença.Conclusões:Estudos epidemiológicos e de coorte sugerem que a vacinação BCG pode prevenir o COVID-19, porém sem uma avaliação mais cuidadosa e detalhada não podemos assumir isso como evidência irrefutável.<br>Background: Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in China by the end of 2019, it has infected more than 93 million humans around the world, overwhelmed health systems worldwide and caused more than 2 million deaths. The easy-spread of the virus and the need for health care professional’s protection raised attention to Bacillus Calmette-Guérin (BCG) vaccine. BCG is known for nonspecific, protective innate immune–boosting effects.Early evidence suggested eventual protection against coronavirus in nations where BCG is part of the national vaccination policy. Methods: After a priori protocol registration in PROSPERO(ID=CRD42020188486), we performed a systematic literature review in PubMed, EMBASE, Web of Science, Clinical Trials.gov and Cochrane Library databases for studies on the use BCG Vaccine for immune- prophylaxis of SARS-CoV illness. Further search was also performed on MedRxiv for pre-prints. Manuscripts selection was conducted according to PRISMA guidelines. The role of BCG vaccination was assessed in terms of incidence and severity of COVID-19 disease. Results: 453 abstracts were initially reviewed and 76 full-text articles were retrieved. From those, 51 studies met the inclusion criteria: 36 original articles and 15 clinical trials. A positive effect of the BCG vaccine on diminishing COVID-19 cases and mortality was verified. Individuals that underwent BCG vaccination are less likely to contract the disease than unvaccinated, are usually asymptomatic and have a lower probability to be hospitalized during the disease course. Conclusions: Epidemiological and cohort studies suggest that BCG vaccination might prevent COVID-19, however without a thoughtful and more detailed evaluation we cannot assume this as irrefutable evidence.

Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia<br>Este trabalho de Final de Mestrado engloba os Relatórios de Estágio e Monografia Intitulada "Virus-like particles based vaccines and their role in the COVID-19 pandemic". No final de 2019, na China, um novo coronavírus foi identificado com o surgimento de uma pneumonia atípica. O mundo rapidamente ficou em alerta devido à alta velocidade com que este vírus se transmitia em todo o mundo. Este novo surto foi rapidamente declarado como uma pandemia.Desde o início surgiu a necessidade de criar uma vacina capaz de acabar com o pesadelo da pandemia.Diversas plataformas foram testadas para o desenvolvimento de vacinas contra a Síndrome Respiratória Aguda Grave Coronavirus 2 (SARS-COV-2), entre as quais vacinas que se baseiam em partículas semelhantes a vírus (VLP). As VLPs, que contam com alguns exemplos já existentes no mercado, como as vacinas para hepatite B e para o vírus do papiloma humano, são nanopartículas com base em proteínas que mimetizam a conformação do vírus, apresentando epítopos à superfície. As vacinas baseadas em VLPs já demonstraram ter inúmeras vantagens, incluindo o facto de serem seguras, não conterem o material genético do vírus e serem muito eficientes em termos de ativação do sistema imunológico. Apesar disso, na formulação destas vacinas muitas vezes aparecem associados adjuvantes.O conhecimento da estrutura do vírus SARS-COV-2 possibilitou o desenvolvimento de partículas que mimetizam este coronavírus.Pelo menos cinco vacinas de VLPs contra o SARS-COV-2 já estão em ensaios clínicos e apresentam potencial para serem bem-sucedidas.Neste texto de revisão, iremos reconhecer o potencial destas partículas que mimetizam os vírus, como elas ativam o nosso sistema imunológico, e desvendar os avanços que as vacinas baseadas em VLPs estão a ter nesta luta que o mundo está a enfrentar contra o COVID-19.Naturalmente, para isso temos que descobrir como funciona este vírus mortal.<br>This Master's Degree document comprises the Internship Reports and Monograph Entitled "Virus-like particles based vaccines and their role in the COVID-19 pandemic".In late 2019, in China, a new coronavirus was identified with the emergence of an atypical pneumonia. The world quickly became in alert due to the high speed with which this virus was being transmitted throughout the world. This new outbreak was quickly declared as a pandemic.From the outset the need arose to create a vaccine capable of putting an end to the pandemic nightmare.Several platforms were tested for the development of vaccines against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2), among which virus like particle (VLP) based vaccines. VLPs, with some examples already on the market such us the vaccines for the hepatitis B and for human papilloma virus, are protein-based nanoparticles that mimic the conformation of the virus, presenting epitopes on their surface. VLP based vaccines have already been shown to have numerous advantages, including the fact that they are safe, do not contain virus genetic material, and very efficient in terms of activating immune system. Despite that, in the formulation of these vaccines they often appear associated with adjuvants. The knowledge of the structure of the SARS-COV-2 has made it possible for the development of particles that mimic these coronavirus.At least, five SARS-COV-2 VLP vaccines are already in clinical trials, and show potential to be successful.In this review text we will recognize the potential of these particles that mimic viruses, and how they activate our immune system, and unravel the advances that VLP based vaccines are having in this fight that the world is facing with the COVID-19. Naturally, for that we have to find out how this deadly virus works.

Coronavirus-2 (SARS-CoV-2) is responsible for the symptoms of COVID-19. Almost every nation has been infected by SARS-CoV-2. The COVID-19 pandemic has prompted researchers to concentrate on the development of a vaccine and treatment techniques by becoming intimately familiar with the infection's biology. In order to minimize COVID-19 mortality and provide global immunity, a highly efficacious SARS-CoV-2 vaccine is imperative. The lengthy and costly process of developing vaccines could be sped up with immunoinformatics techniques. There have been advances in immunoinformatics tools used for reverse vaccinology to develop a SARS-CoV-2 vaccine, including Vaxijen, IEDB, NetCTL 1.2, PEP-FOLD, and studies of the development of MHC-I and II binding epitopes, among others. A drug repurposing strategy would reduce time and cost compared to drug discovery from scratch. It is an effective strategy for leveraging existing medications. Immunoinformatics may help identify T cell and B cell epitopes with more confidence, leading to fewer experiments and higher dependability for identifying vaccine candidates.

Dissertação de Mestrado em Biotecnologia Farmacêutica apresentada à Faculdade de Farmácia<br>Um novo medicamento está sujeito a um rigoroso processo de investigação, desenvolvimento, avaliação e aprovação, por forma a garantir a sua qualidade, segurança e eficácia e o cumprimento dos requisitos exigidos pelas entidades regulamentares competente. No final do ano de 2019, foi identificado um novo coronavírus, o SARS-CoV-2. Este agente etiológico, causador da doença COVID-19, rapidamente se disseminou por todo o mundo, levando a Organização Mundial de Saúde (OMS) a decretar o estado de pandemia COVID-19, a 11 de março de 2020. A situação de emergência gerada, desafiou os sistemas de saúde e as autoridades competentes a nível mundial, exigindo a afetação excecional de recursos técnicos, financeiros e humanos, por forma a combater a crise de saúde pública instalada. O desenvolvimento de uma vacina eficaz contra a COVID-19, foi identificada como a melhor estratégia para suster a pandemia, levando à adoção de estratégias diferenciadas e da convergência de esforços por forma a acelerar o processo de desenvolvimento e introdução no mercado de vacinas contra a COVID-19. Neste estudo pretende-se analisar como decorreu o processo de introdução no mercado das vacinas COVID-19. Serão abordadas as especificidades regulamentares que foram adotadas de modo a permitir a célere aprovação e comercialização destas vacinas.<br>A new drug is subject to a rigorous research, development, evaluation, and approval process to ensure the quality, safety and efficacy of the drug and compliance with the requirements of the relevant regulatory authorities. Late in 2019, a new coronavirus, SARS-CoV-2, was identified. This etiological agent, causing the disease COVID-19, quickly spread throughout the world, leading the World Health Organization (WHO) to decree the state of pandemic COVID-19, on March 11, 2020.This emergency has challenged health systems and competent authorities worldwide, requiring the exceptional allocation of technical, financial, and human resources to combat the public health crisis. The development of an effective vaccine against COVID-19 was identified as the best strategy to halt the pandemic, leading to the adoption of differentiated strategies and the convergence of efforts to accelerate the process of development and market introduction of vaccines against COVID-19. This study aims to analyze how the market introduction process of the COVID-19 vaccines took place. The regulatory specificities that were adopted to allow the rapid approval and marketing of these vaccines will be addressed.

Introdução: A resposta à pandemia provocada pelo vírus SARS-CoV-2 e as vacinas desenvolvidas têm encontrado obstáculos criados pela disseminação de notícias falsas e conspirações propagadas pelo movimento antivacinação nas redes sociais. Desta forma, a hesitação vacinal poderá ter contornos nunca antes vistos, em Portugal, até ao momento. Métodos: Este estudo analisa as publicações, comentários e membros do grupo do Facebook “Anti-VAX Portugal” desde 10 de abril a 10 de outubro de 2020, no decorrer da pandemia. Foi também aplicado um inquérito por questionário online, onde se procura compreender a influência que os conteúdos antivacinais tiveram sobre os utilizadores das redes sociais no processo de decisão de vacinação contra a COVID-19. Resultados: A partir da análise deste grupo, compreendendo 347 membros e com motivações distintas, foram identificadas 440 publicações, das quais 48% são teorias da conspiração. A partilha de publicações contra a vacina para a COVID-19 iniciou-se ainda antes da existência efetiva da vacina. No inquérito online aferimos que a influência dos conteúdos antivacinação na rede social Facebook sobre indivíduos indecisos é quatro vezes superior do que se estes não se deparassem com tais conteúdos. No caso daqueles que se mostravam decididos a não se vacinar contra o vírus SARS-CoV-2, mais de metade foram expostos a conteúdos antivacinação. Conclusão: Este movimento é altamente capacitado para influenciar a opinião de outros através de campanhas antivacinação, realizadas antes da criação da vacina para a COVID-19, e as redes sociais são o veículo ideal para a disseminação e a organização de ações fora do espaço digital.<br>Background: The pandemic by SARS-CoV-2 virus and the vaccines developed will face obstacles created by the dissemination of fake news and conspiracies propagated by the anti-vaccination movement on social media. Thus, the vaccine hesitation will have contours never seen before, in Portugal. Methods: This study analyzes the posts, comments, and members of the Facebook group “Anti-VAX Portugal” from April 10th to October 10th, during the pandemic. As well as the development of an online questionnaire survey where we understand the influence that anti-vaccination content has on social media users to take the COVID-19 vaccine. Results: The analysis of 347 members, with different motivations, culminates in 440 publications where 48% are conspiracy theories. Vaccine sharing for COVID-19 started long before there was one. In the online survey, we verified that the influence of anti-vaccination content on social media, on hesitant individuals, is four times higher than if they had not come across such content. Also, for those who have already decided that they will not be vaccinated against the SARS-CoV-2 virus, more than half were exposed to the contents of the anti-vaccination movement. Conclusion: This movement is highly capable of influencing the opinion of others through anti-vaccination campaigns, carried out before the creation of the vaccine for COVID-19 and social media is the ideal vehicle for the dissemination and organization of actions outside the digital space.

A síndrome respiratória aguda grave, SARS-CoV-2, é um novo coronavírus detetado na China que sofreu uma rápida dissipação a nível mundial, fazendo com que a Organização Mundial de Saúde declarasse pandemia. Esta síndrome apresenta sintomas como febre, tosse, fadiga e cefaleias e, principalmente em doentes de risco e idosos, combinada com outras doenças já existentes, pode evoluir para uma patologia mais grave com consequências maioritariamente a nível do trato respiratório, como dispneia e pneumonia. É transmitida entre humanos sendo que o uso de equipamento de proteção individual e a higienização das mãos com frequência são essenciais para a prevenção da transmissão. Ainda não existem evidências científicas de tratamentos eficazes para a COVID-19, sendo que as principais medidas adotadas são o controlo dos sintomas, efetuado através de terapêuticas primárias e convencionais para os sinais mais ligeiros. Em situações mais graves têm sido utilizados alguns fármacos que demonstraram efeitos positivos, assim como o suporte respiratório em casos mais críticos. Para que o mundo regresse à normalidade que existia antes do início da pandemia (principalmente em termos laboral e social), tornou-se necessário o progresso rápido de estratégias terapêuticas e profiláticas tais como o aparecimento de vacinas seguras e eficazes seguindo a realização de um plano de vacinação mundial. Desde a fase de desenvolvimento de um medicamento até à sua introdução no mercado, pode levar mais de dez anos. Neste caso particular da COVID-19, devido à participação científica mundial e monetária, permitiu a união de esforços para um desenvolvimento em tempo recorde de um bem comum, a vacina. Em menos de um ano esta foi desenvolvida e comercializada tendo sempre em conta que cumpre toda a legislação, respeitando a eficácia mínima e sem comprometer a sua segurança. Nesta revisão bibliográfica, foram feitas várias pesquisas para certificar a regulamentação de suporte e esforços dedicados para a segurança e eficácia das vacinas para o SARSCoV-2, em ensaios clínicos. Os resultados indicam que há uma boa tolerância, transparência e confiança e que toda a comunidade científica e entidades reguladoras estão a trabalhar em conformidade.<br>The severe acute respiratory syndrome, SARS-CoV-2, is a new coronavirus that was detected in China and suffered a rapid dissipation worldwide, making The World Health Organization declare a pandemic situation. This syndrome usually introduces symptoms such as fever, cough, fatigue and headache and, especially in old and high-risk patients, combined with other diseases, can develop into a more serious pathology with consequences mainly at the level of the respiratory tract, such as dyspnea and pneumonia. SARS-CoV-2 infection is transmitted between humans and the use of individual protection equipment and frequent hand hygiene are fundamental to prevent the transmission. There isn’t still scientific evidence of success to treat COVID-19, however the main measures adopted are the control of the symptoms carried out through basic and conventional therapies for the slightest symptoms. Drugs have been used in serious situations, they have shown positive effects as even as respiratory support in more critical cases. To return to normality before the pandemic situation (mainly in labor and social terms), the fast progress has become required in therapeutic and prophylactic measures such as the emergence of safe vaccines and following the achievement of a worldwide vaccination plan. During the medicine development until their introduction on the market, can last more than ten years to be commercialized. In the case of COVID-19, due to the activity worldwide scientific and monetary, it allowed the connection to development of the vaccine, in record time. In less than one year, the vaccine was developed and marketed following the mandatory standards, concerning the minimal effectiveness and without implicating their safety. In this literature review, multiple searches were carried out to certify the support regulation and dedicated efforts to achieve a safety vaccine to prevent SARS-CoV-2, in clinical trials. The results show a good tolerance, transparency and trust and all scientific communities and regulatory authorities are working accordingly.