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2.
Biomater Sci ; 9(22): 7392-7401, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34751685

RESUMO

Advances in the development of modern cancer immunotherapy and immune checkpoint inhibitors have dramatically changed the landscape of cancer treatment. However, most cancer patients are refractory to immune checkpoint inhibitors because of low lymphocytic tumor infiltration and PD-L1 expression. Evidence suggests that viral oncolysis and immune checkpoint inhibitors have a synergistic effect that can improve the response to immune checkpoint inhibitors. In this study, we developed bioengineered cell membrane nanovesicles (PD1-BCMNs) with programmed cell death protein 1 (PD-1) to harbor oncolytic adenovirus (OA) and achieve a combination of immune checkpoint blockade and oncolytic virotherapy in one particle for cancer treatment. PD1-BCMNs could specifically deliver OA to tumor tissue; the infectivity and replication ability of the OA was preserved in the presence of neutralizing antibodies in vitro and in vivo. Selective oncolytic effects with oncolytic adenovirus led to an up-regulated expression of PD-L1 in the tumor microenvironment, turning immunologically 'cold' tumors into immunologically 'hot' tumors, presenting more targets for further enhanced target delivery. Notably, PD1-BCMNs@OA could effectively activate tumor-infiltrating T cells and elicit a strong anti-tumor immune response. Thus, PD1-BCMNs@OA may provide a clinical basis for combining oncolytic virotherapy with checkpoint inhibitors, enhancing the oncolytic adenovirus targeted delivery and significantly enhancing T cell immune responses, resulting in a stronger antitumor immunity response.


Assuntos
Inibidores de Checkpoint Imunológico , Terapia Viral Oncolítica , Adenoviridae/genética , Linhagem Celular Tumoral , Humanos , Imunoterapia
3.
Nat Commun ; 12(1): 6277, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725327

RESUMO

Several COVID-19 vaccines have now been deployed to tackle the SARS-CoV-2 pandemic, most of them based on messenger RNA or adenovirus vectors.The duration of protection afforded by these vaccines is unknown, as well as their capacity to protect from emerging new variants. To provide sufficient coverage for the world population, additional strategies need to be tested. The live pediatric measles vaccine (MV) is an attractive approach, given its extensive safety and efficacy history, along with its established large-scale manufacturing capacity. We develop an MV-based SARS-CoV-2 vaccine expressing the prefusion-stabilized, membrane-anchored full-length S antigen, which proves to be efficient at eliciting strong Th1-dominant T-cell responses and high neutralizing antibody titers. In both mouse and golden Syrian hamster models, these responses protect the animals from intranasal infectious challenge. Additionally, the elicited antibodies efficiently neutralize in vitro the three currently circulating variants of SARS-CoV-2.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Vetores Genéticos , Imunidade , Adenoviridae , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Cricetinae , Citocinas , Feminino , Imunização , Imunização Secundária , Masculino , Vacina contra Sarampo/imunologia , Mesocricetus , Camundongos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
4.
Sci Rep ; 11(1): 20877, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686689

RESUMO

Adenovirus vectors offer a platform technology for vaccine development. The value of the platform has been proven during the COVID-19 pandemic. Although good stability at 2-8 °C is an advantage of the platform, non-cold-chain distribution would have substantial advantages, in particular in low-income countries. We have previously reported a novel, potentially less expensive thermostabilisation approach using a combination of simple sugars and glass micro-fibrous matrix, achieving excellent recovery of adenovirus-vectored vaccines after storage at temperatures as high as 45 °C. This matrix is, however, prone to fragmentation and so not suitable for clinical translation. Here, we report an investigation of alternative fibrous matrices which might be suitable for clinical use. A number of commercially-available matrices permitted good protein recovery, quality of sugar glass and moisture content of the dried product but did not achieve the thermostabilisation performance of the original glass fibre matrix. We therefore further investigated physical and chemical characteristics of the glass fibre matrix and its components, finding that the polyvinyl alcohol present in the glass fibre matrix assists vaccine stability. This finding enabled us to identify a potentially biocompatible matrix with encouraging performance. We discuss remaining challenges for transfer of the technology into clinical use, including reliability of process performance.


Assuntos
Adenoviridae/genética , Vacinas contra Adenovirus/química , Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Potência de Vacina , Adenovirus dos Símios , Materiais Biocompatíveis , Varredura Diferencial de Calorimetria , Vidro , Células HEK293 , Humanos , Luz , Espectroscopia de Ressonância Magnética , Teste de Materiais , Microscopia Confocal , Microscopia Eletrônica de Varredura , Álcool de Polivinil , Vacinas Antirrábicas , Espalhamento de Radiação , Espectroscopia de Infravermelho com Transformada de Fourier , Açúcares/química , Temperatura , Termogravimetria , Trealose/química
5.
Anticancer Res ; 41(10): 4837-4855, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593432

RESUMO

BACKGROUND/AIM: The adenovirus vector- carrying reduced expression in immortalized cell (REIC) gene (Ad-REIC) increases endoplasmic reticulum stress chaperone GRP78/BiP expression and induces the JNK-mediated apoptotic pathway. We aimed to determine whether Ad-REIC-induced apoptotic cell death can trigger immunogenic cell death (ICD). MATERIALS AND METHODS: We examined the emission of damage-associated molecular patterns in vitro and the vaccination effect in vivo. We determined the immunological changes in the tumour microenvironment by putative ICD inducers and the combined effects of immune checkpoint blockade therapies. RESULTS: Ad-REIC induced the release of high-mobility group box 1 and adenosine triphosphate and the translocation of calreticulin in murine mesothelioma AB12 cells. The vaccination effect was elicited by Ad-REIC treatment in vivo. The effect of Ad-REIC was potentiated by anti-cytotoxic T-lymphocyte-associated protein 4 antibody treatment in a murine mesothelioma AB1-HA cell model. CONCLUSION: Ad-REIC induces ICD in malignant mesothelioma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Morte Celular Imunogênica/efeitos dos fármacos , Mesotelioma Maligno/terapia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Trifosfato de Adenosina/metabolismo , Adenoviridae/genética , Animais , Apoptose/efeitos dos fármacos , Antígenos CD8/metabolismo , Calreticulina/metabolismo , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Terapia Combinada , Terapia Genética , Vetores Genéticos , Proteína HMGB1/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Mesotelioma Maligno/imunologia , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Viruses ; 13(10)2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34696497

RESUMO

Respiratory viruses are known to be the most frequent causative mediators of lung infections in humans, bearing significant impact on the host cell signaling machinery due to their host-dependency for efficient replication. Certain cellular functions are actively induced by respiratory viruses for their own benefit. This includes metabolic pathways such as glycolysis, fatty acid synthesis (FAS) and the tricarboxylic acid (TCA) cycle, among others, which are modified during viral infections. Here, we summarize the current knowledge of metabolic pathway modifications mediated by the acute respiratory viruses respiratory syncytial virus (RSV), rhinovirus (RV), influenza virus (IV), parainfluenza virus (PIV), coronavirus (CoV) and adenovirus (AdV), and highlight potential targets and compounds for therapeutic approaches.


Assuntos
Ciclo do Ácido Cítrico/fisiologia , Metabolismo Energético/fisiologia , Ácidos Graxos/biossíntese , Glicólise/fisiologia , Infecções Respiratórias/patologia , Infecções Respiratórias/virologia , Adenoviridae/metabolismo , Coronavirus/metabolismo , Humanos , Orthomyxoviridae/metabolismo , Vírus da Parainfluenza 1 Humana/metabolismo , Vírus Sinciciais Respiratórios/metabolismo , Rhinovirus/metabolismo
7.
Immunol Cell Biol ; 99(10): 1006-1010, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34664303

RESUMO

We hypothesize that thrombosis with thrombocytopenia syndrome recently described after administration of adenovirus-vectored vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs as a result of the unique properties of the adenovirus vectors, which can have widespread biodistribution throughout the body. The antigen is delivered to megakaryocyte cells, which act as part of the primary immune system and distribute the antigen within progeny platelets, also a key component of the immune system. The interaction of the antigen induces preformed antiplatelet factor 4 (PF4) antibodies to bind to PF4-heparan sulfate complexes in the absence of exogenous heparin, at sites where the heparan sulfate concentration in the vascular glycocalyx is optimal for complex formation, causing thrombosis and thrombocytopenia as observed clinically. This hypothesis is testable in cell culture and animal models, and potentially in vivo, and if proven correct has significant implications for vaccine development and our understanding of the links between the coagulation and immune systems.


Assuntos
COVID-19 , Trombocitopenia , Trombose , Vacinas , Adenoviridae , Animais , Humanos , SARS-CoV-2 , Distribuição Tecidual , Vacinação
8.
Cells ; 10(10)2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34685696

RESUMO

As of September 2021, twenty-one anti-COVID-19 vaccines have been approved in the world. Their utilization will expedite an end to the current pandemic. Besides the usual vaccine formats that include inactivated viruses (eight approved vaccines) and protein-based vaccines (four approved vaccines), three new formats have been validated: recombinant adenovirus (six approved vaccines), DNA (one approved vaccine), and messenger RNA (mRNA, two approved vaccines). The latter was the fastest (authorized in 2020 in the EU, the USA, and Switzerland). Most Western countries have reserved or use the protein vaccines, the adenovirus vaccines, and mRNA vaccines. I describe here the different vaccine formats in the context of COVID-19, detail the three formats that are chiefly reserved or used in Europe, Canada, and the USA, and discuss why the mRNA vaccines appear to be the superior format.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , RNA Mensageiro , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Adenoviridae/genética , Animais , Canadá , DNA/genética , Aprovação de Drogas , Europa (Continente) , Humanos , Camundongos , Segurança do Paciente , Estados Unidos
9.
Int J Mol Sci ; 22(19)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34639132

RESUMO

Novel coronavirus SARS-CoV-2 has resulted in a global pandemic with worldwide 6-digit infection rates and thousands of death tolls daily. Enormous efforts are undertaken to achieve high coverage of immunization to reach herd immunity in order to stop the spread of SARS-CoV-2 infection. Several SARS-CoV-2 vaccines based on mRNA, viral vectors, or inactivated SARS-CoV-2 virus have been approved and are being applied worldwide. However, the recent increased numbers of normally very rare types of thromboses associated with thrombocytopenia have been reported, particularly in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. The statistical prevalence of these side effects seems to correlate with this particular vaccine type, i.e., adenoviral vector-based vaccines, but the exact molecular mechanisms are still not clear. The present review summarizes current data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis indicating that coagulopathies, including thromboses, thrombocytopenia, and other related side effects, are correlated to an interplay of the two components in the vaccine, i.e., the spike antigen and the adenoviral vector, with the innate and immune systems, which under certain circumstances can imitate the picture of a limited COVID-19 pathological picture.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Trombocitopenia/etiologia , Trombose/etiologia , Adenoviridae/imunologia , Animais , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Vetores Genéticos/efeitos adversos , Vetores Genéticos/imunologia , Humanos , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/imunologia , Glicoproteína da Espícula de Coronavírus/efeitos adversos , Trombocitopenia/imunologia , Trombose/imunologia , Vacinação/efeitos adversos
10.
BMC Genomics ; 22(1): 777, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34717548

RESUMO

BACKGROUND: Viral vectors, including adenovirus (Ad) and modified vaccinia Ankara (MVA), have gained increasing attention as vaccine platforms in recent years due to their capacity to express antigens from a wide array of pathogens, their rapid induction of humoral and cellular protective immune responses, and their relatively low production costs. In particular, the chimpanzee Ad vector, ChAdOx1, has taken centre stage as a leading COVID-19 vaccine candidate. However, despite mounting data, both clinical and pre-clinical, demonstrating effective induction of adaptive immune responses, the innate immune signals that precede the protective responses that make these vectors attractive vaccine platforms remain poorly understood. RESULTS: In this study, a mouse immunisation model was used to evaluate whole blood gene expression changes 24 h after either a single dose or heterologous prime-boost regimen of an Ad and/or MVA vaccine. We demonstrate through comparative analysis of Ad vectors encoding different antigens that a transgene product-specific gene signature can be discerned from the vector-induced transcriptional response. Expression of genes involved in TLR2 stimulation and γδ T cell and natural killer cell activation were induced after a single dose of Ad, while MVA led to greater expression of type I interferon genes. The order of prime-boost combinations was found to influence the magnitude of the gene expression changes, with MVA/Ad eliciting greater transcriptional perturbation than Ad/MVA. Contrasting the two regimens revealed significant enrichment of epigenetic regulation pathways and augmented expression of MHC class I and II molecules associated with MVA/Ad. CONCLUSION: These data demonstrate that the order in which vaccines from heterologous prime-boost regimens are administered leads to distinct transcriptional responses and may shape the immune response induced by such combinations. The characterisation of early vaccine-induce responses strengthens our understanding of viral vector vaccine mechanisms of action ahead of their characterisation in human clinical trials and are a valuable resource to inform the pre-clinical design of appropriate vaccine constructs for emerging infectious diseases.


Assuntos
COVID-19 , Vacinas Virais , Adenoviridae/genética , Animais , Vacinas contra COVID-19 , Epigênese Genética , Vetores Genéticos/genética , Humanos , Imunização , Camundongos , SARS-CoV-2
11.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638863

RESUMO

Oncolytic adenovirus therapy is gaining importance as a novel treatment option for the management of various cancers. Different concepts of modification within the adenovirus vector have been identified that define the mode of action against and the interaction with the tumour. Adenoviral vectors allow for genetic manipulations that restrict tumour specificity and also the expression of specific transgenes in order to support the anti-tumour effect. Additionally, replication of the virus and reinfection of neighbouring tumour cells amplify the therapeutic effect. Another important aspect in oncolytic adenovirus therapy is the virus induced cell death which is a process that activates the immune system against the tumour. This review describes which elements in adenovirus vectors have been identified for modification not only to utilize oncolytic adenovirus vectors into conditionally replicating adenoviruses (CRAds) that allow replication specifically in tumour cells but also to confer specific characteristics to these viruses. These advances in development resulted in clinical trials that are summarized based on the conceptual design.


Assuntos
Adenoviridae/genética , Vetores Genéticos/genética , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Adenoviridae/imunologia , Animais , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Vetores Genéticos/imunologia , Humanos , Neoplasias/genética , Neoplasias/imunologia , Vírus Oncolíticos/imunologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Replicação Viral/genética , Replicação Viral/imunologia
12.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638909

RESUMO

Hepatitis B virus (HBV) chronically infects more than 240 million people worldwide, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Genome editing using CRISPR/Cas9 could provide new therapies because it can directly disrupt HBV genomes. However, because HBV genome sequences are highly diverse, the identical target sequence of guide RNA (gRNA), 20 nucleotides in length, is not necessarily present intact in the target HBV DNA in heterogeneous patients. Consequently, possible genome-editing drugs would be effective only for limited numbers of patients. Here, we show that an adenovirus vector (AdV) bearing eight multiplex gRNA expression units could be constructed in one step and amplified to a level sufficient for in vivo study with lack of deletion. Using this AdV, HBV X gene integrated in HepG2 cell chromosome derived from a heterogeneous patient was cleaved at multiple sites and disrupted. Indeed, four targets out of eight could not be cleaved due to sequence mismatches, but the remaining four targets were cleaved, producing irreversible deletions. Accordingly, the diverse X gene was disrupted at more than 90% efficiency. AdV containing eight multiplex gRNA units not only offers multiple knockouts of genes, but could also solve the problems of heterogeneous targets and escape mutants in genome-editing therapy.


Assuntos
Adenoviridae/genética , Sistemas CRISPR-Cas , Edição de Genes/métodos , Vírus da Hepatite B/genética , RNA Guia/genética , Transativadores/genética , Proteínas Virais Reguladoras e Acessórias/genética , Adenoviridae/fisiologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Vetores Genéticos/genética , Células HEK293 , Células Hep G2 , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/genética , Hepatite B Crônica/terapia , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/virologia , RNA Guia/metabolismo , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Replicação Viral/genética
13.
Microbiol Spectr ; 9(2): e0083121, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34668725

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), has infected all age groups and disproportionately impacted vulnerable populations globally. Polymicrobial infections may play an important role in the development of SARS-CoV-2 infection in susceptible hosts. These coinfections may increase the risk of disease severity and pose challenges to the diagnosis, treatment, and prognosis of COVID-19. There have been limited SARS-CoV-2 coinfection studies. In this retrospective study, residual nucleic acid extracts from 796 laboratory-confirmed COVID-19-positive specimens, collected between March 2020 and February 2021, were analyzed using a Luminex NxTAG respiratory pathogen panel (RPP). Of these, 745 returned valid results and were used for analysis; 53 (7.1%) were positive for one or more additional pathogens. Six different respiratory viruses were detected among the 53 SARS-CoV-2-positive patient specimens, and 7 of those specimens tested positive for more than one additional respiratory virus. The most common pathogens include rhinovirus/enterovirus (RV/EV) (n = 22, 41.51%), human metapneumovirus (hMPV) (n = 18, 33.9%), and adenovirus (n = 12, 22.6%). Interestingly, there were no SARS-CoV-2 coinfections involving influenza A or influenza B in the study specimens. The median age of the SARS-CoV-2-positive patients with coinfections was 38 years; 53% identified as female, and 47% identified as male. Based on our retrospective analysis, respiratory coinfections associated with SARS-CoV-2-positive patients were more common in young children (≤9 years old), with white being the most common race. Our findings will likely prompt additional investigation of polymicrobial infection associated with SARS-CoV-2 during seasonal respiratory pathogen surveillance by public health laboratories. IMPORTANCE This examination of respiratory pathogen coinfections in SARS-CoV-2 patients will likely shed light on our understanding of polymicrobial infection associated with COVID-19. Our results should prompt public health authorities to improve seasonal respiratory pathogen surveillance practices and address the risk of disease severity.


Assuntos
COVID-19/complicações , Coinfecção/virologia , Infecções Respiratórias/complicações , Infecções Respiratórias/virologia , Adenoviridae/genética , Adenoviridae/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Enterovirus/genética , Enterovirus/isolamento & purificação , Feminino , Humanos , Masculino , Metapneumovirus/genética , Metapneumovirus/isolamento & purificação , Pessoa de Meia-Idade , Estudos Retrospectivos , Rhinovirus/genética , Rhinovirus/isolamento & purificação , SARS-CoV-2/genética , Wisconsin , Adulto Jovem
15.
Sci Rep ; 11(1): 17725, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489497

RESUMO

Gene electrotransfer is an attractive method of non-viral gene delivery. However, the mechanism of DNA penetration across the plasma membrane is widely discussed. To explore this process for even larger structures, like viruses, we applied various combinations of short/long and high/low-amplitude electric pulses to L929 cells, mixed with a human adenovirus vector expressing GFP. We observed a transgene expression increase, both in the number of GFP-converted cells and GFP levels, when we added a low-voltage/millisecond-pulse treatment to the adenovirus/cell mixture. This increase, reflecting enhanced virus penetration, was proportional to the applied electric field amplitude and pulse number, but was not associated with membrane permeabilization, nor to direct cell modifications. We demonstrated that this effect is mainly due to adenovirus particle interactions with aggregated aluminum particles released from energized electrodes. Indeed, after centrifugation of the pulsed viral suspension and later on addition to cells, the activity was found mainly associated with the aluminum aggregates concentrated in the lower fraction and was proportional to generated quantities. Overall, this work focused on the use of electrotransfer to facilitate the adenovirus entry into cell, demonstrating that modifications of the penetrating agent can be more important than modifications of the target cell for transfer efficacy.


Assuntos
Adenoviridae , Alumínio , Eletroporação/métodos , Técnicas de Transferência de Genes , Animais , Linhagem Celular , Estimulação Elétrica , Fibroblastos , Camundongos
19.
Clin Appl Thromb Hemost ; 27: 10760296211040110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34541935

RESUMO

Since the outbreak of Covid-19 in December, 2019, scientists worldwide have been committed to developing COVID-19 vaccines. Only when most people have immunity to SARS-CoV-2, COVID-19 can reduce even wholly overcome. So far, nine kinds of COVID-19 vaccines have passed the phase III clinical trials and have approved for use. At the same time, adverse reactions after COVID-19 vaccination have also reported. This paper focuses on the adverse effects of thrombosis and thrombocytopenia caused by the COVID-19 vaccine, especially the adenovirus-vector vaccine from AstraZeneca and Pfizer, and discusses its mechanism and possible countermeasures.


Assuntos
Adenoviridae/genética , Vacinas contra COVID-19/efeitos adversos , Vetores Genéticos , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente , Vacinação/efeitos adversos , Anticorpos/sangue , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Humanos , Fator Plaquetário 4/imunologia , Medição de Risco , Fatores de Risco , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombose/sangue , Trombose/imunologia
20.
Front Immunol ; 12: 728513, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484238

RESUMO

VITT is a rare, life-threatening syndrome characterized by thrombotic symptoms in combination with thrombocytopenia, which may occur in individuals receiving the first administration of adenoviral non replicating vectors (AVV) anti Covid19 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by high levels of serum IgG that bind PF4/polyanion complexes, thus triggering platelet activation. Therefore, identification of the fine pathophysiological mechanism by which vaccine components trigger platelet activation is mandatory. Herein, we propose a multistep mechanism involving both the AVV and the neo-synthetized Spike protein. The former can: i) spread rapidly into blood stream, ii), promote the early production of high levels of IL-6, iii) interact with erythrocytes, platelets, mast cells and endothelia, iv) favor the presence of extracellular DNA at the site of injection, v) activate platelets and mast cells to release PF4 and heparin. Moreover, AVV infection of mast cells may trigger aberrant inflammatory and immune responses in people affected by the mast cell activation syndrome (MCAS). The pre-existence of natural antibodies binding PF4/heparin complexes may amplify platelet activation and thrombotic events. Finally, neosynthesized Covid 19 Spike protein interacting with its ACE2 receptor on endothelia, platelets and leucocyte may trigger further thrombotic events unleashing the WITT syndrome.


Assuntos
Anticorpos/efeitos adversos , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Púrpura Trombocitopênica Idiopática/fisiopatologia , Adenoviridae/genética , Animais , Plaquetas/imunologia , Plaquetas/patologia , Vacinas contra COVID-19/imunologia , Modelos Animais de Doenças , Vetores Genéticos , Humanos , Camundongos , Ativação Plaquetária/imunologia , Fator Plaquetário 4 , Coelhos
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