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1.
Nat Commun ; 12(1): 5215, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471122

RESUMO

Achieving sufficient worldwide vaccination coverage against SARS-CoV-2 will require additional approaches to currently approved viral vector and mRNA vaccines. Subunit vaccines may have distinct advantages when immunizing vulnerable individuals, children and pregnant women. Here, we present a new generation of subunit vaccines targeting viral antigens to CD40-expressing antigen-presenting cells. We demonstrate that targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to CD40 (αCD40.RBD) induces significant levels of specific T and B cells, with long-term memory phenotypes, in a humanized mouse model. Additionally, we demonstrate that a single dose of the αCD40.RBD vaccine, injected without adjuvant, is sufficient to boost a rapid increase in neutralizing antibodies in convalescent non-human primates (NHPs) exposed six months previously to SARS-CoV-2. Vaccine-elicited antibodies cross-neutralize different SARS-CoV-2 variants, including D614G, B1.1.7 and to a lesser extent B1.351. Such vaccination significantly improves protection against a new high-dose virulent challenge versus that in non-vaccinated convalescent animals.


Assuntos
Antígenos CD40/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Convalescença , Humanos , Macaca , Camundongos , Mutação , Domínios Proteicos , Reinfecção/prevenção & controle , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Linfócitos T/imunologia , Vacinação , Vacinas de Subunidades/imunologia
2.
Front Immunol ; 12: 692729, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421902

RESUMO

Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19.


Assuntos
Vacina BCG/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas , SARS-CoV-2/imunologia , Adulto , COVID-19/imunologia , COVID-19/prevenção & controle , Células Cultivadas , Técnicas de Cocultura , Feminino , Citometria de Fluxo , Humanos , Masculino , Análise de Sequência de Proteína , Homologia de Sequência , Vacinas de Subunidades/imunologia , Adulto Jovem
3.
Sci Rep ; 11(1): 15431, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326355

RESUMO

Currently, no approved vaccine is available against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes severe respiratory disease. The spike glycoprotein is typically considered a suitable target for MERS-CoV vaccine candidates. A computational strategy can be used to design an antigenic vaccine against a pathogen. Therefore, we used immunoinformatics and computational approaches to design a multi-epitope vaccine that targets the spike glycoprotein of MERS-CoV. After using numerous immunoinformatics tools and applying several immune filters, a poly-epitope vaccine was constructed comprising cytotoxic T-cell lymphocyte (CTL)-, helper T-cell lymphocyte (HTL)-, and interferon-gamma (IFN-γ)-inducing epitopes. In addition, various physicochemical, allergenic, and antigenic profiles were evaluated to confirm the immunogenicity and safety of the vaccine. Molecular interactions, binding affinities, and the thermodynamic stability of the vaccine were examined through molecular docking and dynamic simulation approaches, during which we identified a stable and strong interaction with Toll-like receptors (TLRs). In silico immune simulations were performed to assess the immune-response triggering capabilities of the vaccine. This computational analysis suggested that the proposed vaccine candidate would be structurally stable and capable of generating an effective immune response to combat viral infections; however, experimental evaluations remain necessary to verify the exact safety and immunogenicity profile of this vaccine.


Assuntos
Epitopos/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Vacinas/imunologia , Biologia Computacional , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Humanos , Imunogenicidade da Vacina/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Modelos Moleculares , Simulação de Acoplamento Molecular , Filogenia , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas/farmacologia , Vacinas de Subunidades/imunologia , Vacinas Virais/imunologia
4.
Int J Biol Macromol ; 183: 2162-2173, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34102236

RESUMO

Effective controls on viral infections rely on the continuous development in vaccine technology. Nanoparticle (NP) antigens are highly immunogenic based on their unique physicochemical properties, making them molecular scaffolds to present soluble vaccine antigens. Here, viral targets (113-354 aas) were genetically fused to N terminal of mi3, a protein that self-assembles into nanoparticles composed of 60 subunits. With transmission electron microscopy, it was confirmed that target-mi3 fusion proteins which have insertions of up to 354 aas in N terminal form intact NPs. Moreover, viral targets are surface-displayed on NPs as indicated in dynamic light scattering. NPs exhibit perfect stability after long-term storage at room temperature. Moreover, SP-E2-mi3 NPs enhance antigen uptake and maturation in dendritic cells (DCs) via up-regulating marker molecules and immunostimulatory cytokines. Importantly, in a mouse model, SP-E2-mi3 nanovaccines against Classical swine fever virus (CSFV) remarkably improved CSFV-specific neutralizing antibodies (NAbs) and cellular immunity related cytokines (IFN-γ and IL-4) as compared to monomeric E2. Specially, improved NAb response with more than tenfold increase in NAb titer against both CSFV Shimen and HZ-08 strains indicated better cross-protection against different genotypes. Collectively, this structure-based, self-assembling NP provides an attractive platform to improve the potency of subunit vaccine for emerging pathogens.


Assuntos
Antígenos Virais/farmacologia , Vírus da Febre Suína Clássica/imunologia , Peste Suína Clássica/prevenção & controle , Imunogenicidade da Vacina , Nanopartículas , Vacinas Virais/farmacologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Antígenos Virais/genética , Antígenos Virais/imunologia , Células Cultivadas , Peste Suína Clássica/sangue , Peste Suína Clássica/imunologia , Peste Suína Clássica/virologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Estabilidade de Medicamentos , Feminino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Suínos , Temperatura , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacologia , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/farmacologia , Vacinas Virais/imunologia
5.
Theranostics ; 11(15): 7308-7321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158852

RESUMO

Dendritic cells (DCs) can process the antigens of cancer vaccine and thus stimulate the CD8+ T cells to recognize and kill the tumor cells that express these antigens. However, lack of promising carriers for presenting the antigens to DCs is one of the main barriers to the development of clinically effective cancer vaccines. Another limitation is the risk of inflammatory side effects induced by the adjuvants. It is still unclear how we can develop ideal adjuvant-free DC vaccine carriers without adjuvants. Methods: A 12-mer peptide carrier (CBP-12) with high affinity for Clec9a expressed on DCs was developed using an in silico rational optimization method. The therapeutic effects of the adjuvant-free vaccine comprising CBP-12 and exogenous or endogenous antigenic peptides were investigated in terms of antigen cross-presentation efficacy, specific cytotoxic T lymphocyte response, and antitumor activity. We also explored the mechanism involved in the antitumor effects of the adjuvant-free CBP-12 vaccine. Finally, we assessed the effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Results: Here, we developed CBP-12 as a vaccine carrier that enhanced the uptake and cross-presentation of the antigens, thus inducing strong CD8+ T cell responses and antitumor effects in both anti-PD-1-responsive (B16-OVA) and -resistant (B16) models, even in adjuvant-free conditions. CBP-12 bound to and activated Clec9a, thereby stimulating Clec9a+ DC to product IL-21, but not IL-12 by activating of Syk. The antitumor effects of the CBP-12 conjugated peptide vaccines could be blocked by an IL-21 neutralizing antibody. We also observed the synergistic antitumor effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Conclusions: CBP-12 could serve as an adjuvant-free peptide vaccine carrier for cancer immunotherapy.


Assuntos
Vacinas Anticâncer , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos , Interleucinas/imunologia , Lectinas Tipo C/imunologia , Melanoma Experimental/imunologia , Peptídeos , Receptores Imunológicos/imunologia , Transdução de Sinais/efeitos dos fármacos , Quinase Syk/imunologia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Feminino , Interleucinas/genética , Lectinas Tipo C/genética , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos , Camundongos Knockout , Peptídeos/imunologia , Peptídeos/farmacologia , Receptores Imunológicos/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Quinase Syk/genética , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacologia
6.
Vaccine ; 39(29): 3879-3891, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34099328

RESUMO

A major challenge for HIV vaccine development is to raise anti-envelope antibodies capable of recognizing and neutralizing diverse strains of HIV-1. Accordingly, a full length single chain (FLSC) of gp120-CD4 chimeric vaccine construct was designed to present a highly conserved CD4-induced (CD4i) HIV-1 envelope structure that elicits cross-reactive anti-envelope humoral responses and protective immunity in animal models of HIV infection. IHV01 is the FLSC formulated in aluminum phosphate adjuvant. We enrolled 65 healthy adult volunteers in this first-in-human phase 1a randomized, double-blind, placebo-controlled study with three dose-escalating cohorts (75 µg, 150 µg, and 300 µg doses). Intramuscular injections were given on weeks 0, 4, 8, and 24. Participants were followed for an additional 24 weeks after the last immunization. The overall incidence of adverse events (AEs) was not significantly different between vaccinees and controls. The majority (89%) of vaccine-related AE were mild. The most common vaccine-related adverse event was injection site pain. There were no vaccine-related serious AE, discontinuation due to AE, intercurrent HIV infection, or significant decreases in CD4 count. By the final vaccination, all vaccine recipients developed antibodies against IHV01 and demonstrated anti-CD4i epitope antibodies. The elicited antibodies reacted with CD4 non-liganded Env antigens from diverse HIV-1 strains. Antibody-dependent cell-mediated cytotoxicity against heterologous infected cells or gp120 bound to CD4+ cells was evident in all cohorts as were anti-gp120 T-cell responses. IHV01 vaccine was safe, well tolerated, and immunogenic at all doses tested. The vaccine raised broadly reactive humoral responses against conserved CD4i epitopes on gp120 that mediates antiviral functions.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV , Imunogenicidade da Vacina , Vacinas contra a AIDS/efeitos adversos , Adulto , Animais , Antígenos CD4 , Anticorpos Anti-HIV , Proteína gp120 do Envelope de HIV , Infecções por HIV/prevenção & controle , HIV-1 , Humanos , Vacinas de Subunidades/efeitos adversos , Vacinas de Subunidades/imunologia
7.
Fish Shellfish Immunol ; 115: 205-211, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34153431

RESUMO

Infectious pancreatic necrosis (IPN) is a highly contagious disease causing high mortality in juvenile trouts. Since there is no effective way to treatment against IPNV, early diagnosis and prevention play an important role in combating the disease. The different types of IPNV vaccines (inactive, live, recombinant, DNA, etc) have been produced from local isolates and have been used in developed countries. In Turkey, there is no commercial licensed vaccines against IPNV. Due to this reason, IPNV vaccine is needed in Turkey. The production of recombinant VP2 subunit vaccine (IPNV-VP2) and inactivated whole particle virus vaccine (IPNV-WPV) were attempted from selected isolate belong to sp serotype. For this purpose; the virus was produced in RTG-2 cell line and RT-PCR amplification was performed by using primers with restriction enzymes. The whole VP2 gene was cloned into a plasmid vector and VP2 was expressed by using E. coli expression system. A trial was conducted to determine the immunity ability of IPNV-VP2 and IPNV-WPV in rainbow trout. According to the SN50 assay, the IPNV-WPV stimulates immune response faster than the IPNV-VP2 vaccine. Besides, the relative percent of Survive (RPS) was detected as 79% in fish vaccinated with IPNV-WPV and 70% in fish vaccinated with IPNV-VP2. Thus, we can say that the recombinant vaccine of IPNV-VP2 is almost protected against IPNV infection as well as the inactive vaccine.


Assuntos
Infecções por Birnaviridae/veterinária , Doenças dos Peixes/imunologia , Vírus da Necrose Pancreática Infecciosa/imunologia , Oncorhynchus mykiss/imunologia , Proteínas Estruturais Virais/imunologia , Vacinas Virais/imunologia , Animais , Infecções por Birnaviridae/imunologia , Escherichia coli/genética , Microrganismos Geneticamente Modificados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas de Subunidades/imunologia
8.
Int Immunopharmacol ; 96: 107763, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34162141

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the rapidly spreading pandemic COVID-19 in the world. As an effective therapeutic strategy is not introduced yet and the rapid genetic variations in the virus, there is an emerging necessity to design, evaluate and apply effective new vaccines. An acceptable vaccine must elicit both humoral and cellular immune responses, must have the least side effects and the storage and transport systems should be available and affordable for all countries. These vaccines can be classified into different types: inactivated vaccines, live-attenuated virus vaccines, subunit vaccines, virus-like particles (VLPs), nucleic acid-based vaccines (DNA and RNA) and recombinant vector-based vaccines (replicating and non-replicating viral vector). According to the latest update of the WHO report on April 2nd, 2021, at least 85 vaccine candidates were being studied in clinical trial phases and 184 candidate vaccines were being evaluated in pre-clinical stages. In addition, studies have shown that other vaccines, including the Bacillus Calmette-Guérin (BCG) vaccine and the Plant-derived vaccine, may play a role in controlling pandemic COVID-19. Herein, we reviewed the different types of COVID-19 candidate vaccines that are currently being evaluated in preclinical and clinical trial phases along with advantages, disadvantages or adverse reactions, if any.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Vacina BCG/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Vacinas de DNA/imunologia , Vacinas de Produtos Inativados/imunologia , Vacinas de Subunidades/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas Virais/imunologia
9.
Front Immunol ; 12: 641447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108961

RESUMO

The newly emerged novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 has proven to be a threat to the human race globally, thus, vaccine development against SARS-CoV-2 is an unmet need driving mass vaccination efforts. The receptor binding domain of the spike protein of this coronavirus has multiple neutralizing epitopes and is associated with viral entry. Here we have designed and characterized the SARS-CoV-2 spike protein fragment 330-526 as receptor binding domain 330-526 (RBD330-526) with two native glycosylation sites (N331 and N343); as a potential subunit vaccine candidate. We initially characterized RBD330-526 biochemically and investigated its thermal stability, humoral and T cell immune response of various RBD protein formulations (with or without adjuvant) to evaluate the inherent immunogenicity and immunomodulatory effect. Our result showed that the purified RBD immunogen is stable up to 72 h, without any apparent loss in affinity or specificity of interaction with the ACE2 receptor. Upon immunization in mice, RBD generates a high titer humoral response, elevated IFN-γ producing CD4+ cells, cytotoxic T cells, and robust neutralizing antibodies against live SARS-CoV-2 virus. Our results collectively support the potential of RBD330-526 as a promising vaccine candidate against SARS-CoV-2.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/administração & dosagem , Imunidade Humoral/efeitos dos fármacos , Imunogenicidade da Vacina , Fragmentos de Peptídeos/administração & dosagem , Glicoproteína da Espícula de Coronavírus/administração & dosagem , Células Th1/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Animais , Biomarcadores/sangue , Vacinas contra COVID-19/imunologia , Chlorocebus aethiops , Estabilidade de Medicamentos , Glicosilação , Células HEK293 , Humanos , Imunização , Interferon gama/sangue , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/imunologia , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Glicoproteína da Espícula de Coronavírus/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Células Vero
10.
Adv Sci (Weinh) ; 8(16): e2100985, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34176237

RESUMO

COVID-19 is disastrous to global health and the economy. SARS-CoV-2 infection exhibits similar clinical symptoms and immunopathological sequelae to SARS-CoV infection. Therefore, much of the developmental progress on SARS-CoV vaccines can be utilized for the development of SARS-CoV-2 vaccines. Careful antigen selection during development is always of utmost importance for the production of effective vaccines that do not compromise recipient safety. This holds especially true for SARS-CoV vaccines, as several immunopathological disorders are associated with the activity of structural and nonstructural proteins encoded in the virus's genetic material. Whole viral protein and RNA-encoding full-length proteins contain both protective and "dangerous" sequences, unless pathological fragments are deleted. In light of recent advances, peptide vaccines may present a very safe and effective alternative. Peptide vaccines can avoid immunopathological pro-inflammatory sequences, focus immune responses on neutralizing immunogenic epitopes, avoid off-target antigen loss, combine antigens with different protective roles or mechanisms, even from different viral proteins, and avoid mutant escape by employing highly conserved cryptic epitopes. In this review, an attempt is made to exploit the similarities between SARS-CoV and SARS-CoV-2 in vaccine antigen screening, with particular attention to the pathological and immunogenic properties of SARS proteins.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas Virais/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Humanos , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Vacinas Virais/administração & dosagem
11.
Curr Opin Virol ; 49: 52-57, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34049261

RESUMO

SARS-CoV-2 has been detected in more than 141 million people and caused more than 3 million deaths worldwide. To reduce the additional loss of millions of lives until natural immunity is reached, researchers have focused on the only known method to stop the COVID-19 pandemic: vaccines. The pandemic has propelled high-speed vaccine development, some based on novel technology previously not utilized in the vaccine field. The new technology opens new possibilities and comes with challenges because the long-term performance of the new platforms is unknown. Here we review the current leading vaccine candidates against COVID-19 and outline the advantages and disadvantages as well as the unknowns of each candidate.


Assuntos
Pesquisa Biomédica , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Adenoviridae/genética , Pesquisa Biomédica/estatística & dados numéricos , Pesquisa Biomédica/tendências , COVID-19/epidemiologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/genética , Humanos , Mutação , SARS-CoV-2/genética , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/efeitos adversos , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
12.
Epidemiol Infect ; 149: e136, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34032200

RESUMO

Brucellosis is one of the most serious and widespread zoonotic diseases, which seriously threatens human health and the national economy. This study was based on the T/B dominant epitopes of Brucella outer membrane protein 22 (Omp22), outer membrane protein 19 (Omp19) and outer membrane protein 28 (Omp28), with bioinformatics methods to design a safe and effective multi-epitope vaccine. The amino acid sequences of the proteins were found in the National Center for Biotechnology Information (NCBI) database, and the signal peptides were predicted by the SignaIP-5.0 server. The surface accessibility and hydrophilic regions of proteins were analysed with the ProtScale software and the tertiary structure model of the proteins predicted by I-TASSER software and labelled with the UCSF Chimera software. The software COBEpro, SVMTriP and BepiPred were used to predict B cell epitopes of the proteins. SYFPEITHI, RANKpep and IEDB were employed to predict T cell epitopes of the proteins. The T/B dominant epitopes of three proteins were combined with HEYGAALEREAG and GGGS linkers, and carriers sequences linked to the N- and C-terminus of the vaccine construct with the help of EAAAK linkers. Finally, the tertiary structure and physical and chemical properties of the multi-epitope vaccine construct were analysed. The allergenicity, antigenicity and solubility of the multi-epitope vaccine construct were 7.37-11.30, 0.788 and 0.866, respectively. The Ramachandran diagram of the mock vaccine construct showed 96.0% residues within the favoured and allowed range. Collectively, our results showed that this multi-epitope vaccine construct has a high-quality structure and suitable characteristics, which may provide a theoretical basis for future laboratory experiments.


Assuntos
Vacina contra Brucelose/química , Brucella/imunologia , Epitopos de Linfócito B/química , Epitopos de Linfócito T/química , Sequência de Aminoácidos , Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/imunologia , Vacina contra Brucelose/imunologia , Brucelose/prevenção & controle , Biologia Computacional , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Humanos , Imunogenicidade da Vacina , Modelos Moleculares , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Solubilidade , Vacinas de Subunidades/química , Vacinas de Subunidades/imunologia
13.
Nature ; 595(7865): 96-100, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34040257

RESUMO

Trypanosomes are protozoan parasites that cause infectious diseases, including African trypanosomiasis (sleeping sickness) in humans and nagana in economically important livestock1,2. An effective vaccine against trypanosomes would be an important control tool, but the parasite has evolved sophisticated immunoprotective mechanisms-including antigenic variation3-that present an apparently insurmountable barrier to vaccination. Here we show, using a systematic genome-led vaccinology approach and a mouse model of Trypanosoma vivax infection4, that protective invariant subunit vaccine antigens can be identified. Vaccination with a single recombinant protein comprising the extracellular region of a conserved cell-surface protein that is localized to the flagellum membrane (which we term 'invariant flagellum antigen from T. vivax') induced long-lasting protection. Immunity was passively transferred with immune serum, and recombinant monoclonal antibodies to this protein could induce sterile protection and revealed several mechanisms of antibody-mediated immunity, including a major role for complement. Our discovery identifies a vaccine candidate for an important parasitic disease that has constrained socioeconomic development in countries in sub-Saharan Africa5, and provides evidence that highly protective vaccines against trypanosome infections can be achieved.


Assuntos
Antígenos de Protozoários/imunologia , Vacinas Protozoárias/imunologia , Trypanosoma vivax/imunologia , Tripanossomíase Africana/imunologia , Tripanossomíase Africana/prevenção & controle , Animais , Antígenos de Protozoários/química , Proteínas do Sistema Complemento/imunologia , Sequência Conservada/imunologia , Modelos Animais de Doenças , Feminino , Flagelos/química , Flagelos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Protozoárias/química , Fatores de Tempo , Trypanosoma vivax/química , Trypanosoma vivax/citologia , Tripanossomíase Africana/parasitologia , Vacinas de Subunidades/química , Vacinas de Subunidades/imunologia
14.
Cell Res ; 31(7): 732-741, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34021265

RESUMO

SARS-CoV-2 variants could induce immune escape by mutations on the receptor-binding domain (RBD) and N-terminal domain (NTD). Here we report the humoral immune response to circulating SARS-CoV-2 variants, such as 501Y.V2 (B.1.351), of the plasma and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine), ZF2001 (RBD-subunit vaccine) and natural infection. Among 86 potent NAbs identified by high-throughput single-cell VDJ sequencing of peripheral blood mononuclear cells from vaccinees and convalescents, near half anti-RBD NAbs showed major neutralization reductions against the K417N/E484K/N501Y mutation combination, with E484K being the dominant cause. VH3-53/VH3-66 recurrent antibodies respond differently to RBD variants, and K417N compromises the majority of neutralizing activity through reduced polar contacts with complementarity determining regions. In contrast, the 242-244 deletion (242-244Δ) would abolish most neutralization activity of anti-NTD NAbs by interrupting the conformation of NTD antigenic supersite, indicating a much less diversity of anti-NTD NAbs than anti-RBD NAbs. Plasma of convalescents and CoronaVac vaccinees displayed comparable neutralization reductions against pseudo- and authentic 501Y.V2 variants, mainly caused by E484K/N501Y and 242-244Δ, with the effects being additive. Importantly, RBD-subunit vaccinees exhibit markedly higher tolerance to 501Y.V2 than convalescents, since the elicited anti-RBD NAbs display a high diversity and are unaffected by NTD mutations. Moreover, an extended gap between the third and second doses of ZF2001 leads to better neutralizing activity and tolerance to 501Y.V2 than the standard three-dose administration. Together, these results suggest that the deployment of RBD-vaccines, through a third-dose boost, may be ideal for combating SARS-CoV-2 variants when necessary, especially for those carrying mutations that disrupt the NTD supersite.


Assuntos
Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/farmacologia , COVID-19/imunologia , COVID-19/prevenção & controle , Imunidade Humoral , SARS-CoV-2/imunologia , Vacinas de Produtos Inativados/farmacologia , Animais , Anticorpos Neutralizantes/sangue , COVID-19/sangue , Vacinas contra COVID-19/imunologia , Linhagem Celular , Células HEK293 , Humanos , Modelos Moleculares , Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de Produtos Inativados/imunologia , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacologia
15.
Nat Commun ; 12(1): 2633, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976149

RESUMO

Ebola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. Here, we first investigate the contribution of the stalk and heptad repeat 1-C (HR1C) regions to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increase trimer yield, whereas alterations of HR1C exert a more complex effect on thermostability. Crystal structures are determined to validate two rationally designed GPΔmuc trimers in their unliganded state. We then display a modified GPΔmuc trimer on reengineered protein nanoparticles that encapsulate a layer of locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicit cross-ebolavirus NAbs, as well as non-NAbs that enhance pseudovirus infection. Repertoire sequencing reveals quantitative profiles of vaccine-induced B-cell responses. This study demonstrates a promising vaccine strategy for filoviruses, such as EBOV, based on GP stabilization and nanoparticle display.


Assuntos
Vacinas contra Ebola/administração & dosagem , Glicoproteínas/administração & dosagem , Doença pelo Vírus Ebola/terapia , Proteínas Virais/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Antígenos Virais/administração & dosagem , Antígenos Virais/genética , Antígenos Virais/imunologia , Antígenos Virais/ultraestrutura , Linfócitos B/imunologia , Cristalografia por Raios X , Modelos Animais de Doenças , Vacinas contra Ebola/genética , Vacinas contra Ebola/imunologia , Ebolavirus/genética , Ebolavirus/imunologia , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/ultraestrutura , Feminino , Glicoproteínas/genética , Glicoproteínas/imunologia , Glicoproteínas/ultraestrutura , Doença pelo Vírus Ebola/sangue , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Camundongos , Nanopartículas/química , Domínios Proteicos/genética , Domínios Proteicos/imunologia , Engenharia de Proteínas , Multimerização Proteica/genética , Multimerização Proteica/imunologia , Estabilidade Proteica , Coelhos , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/ultraestrutura
16.
Nat Commun ; 12(1): 2626, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976179

RESUMO

By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias/imunologia , Vírus Oncolíticos/genética , Poli I-C/administração & dosagem , Poli I-C/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vírus Vaccinia , Vírus da Estomatite Vesicular Indiana , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Front Immunol ; 12: 629480, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868248

RESUMO

Passive immunization with specific egg yolk antibodies (immunoglobulin Y, IgY) is emerging as a promising alternative to antibiotics to control bacterial infections. Recently, we developed a novel conjugate vaccine that could trigger a strong immune response in rabbits directed against enterobactin (Ent), a highly conserved siderophore molecule utilized by different Gram-negative pathogens. However, induction of Ent-specific antibodies appeared to be affected by the choice of animal host and vaccination regimen. It is still unknown if the Ent conjugate vaccine can trigger a specific immune response in layers for the purpose of production of anti-Ent egg yolk IgY. In this study, three chicken vaccination trials with different regimens were performed to determine conditions for efficient production of anti-Ent egg yolk IgY. Purified Ent was conjugated to three carrier proteins, keyhole limpet hemocyanin (KLH), bovine serum albumin (BSA) and CmeC (a subunit vaccine candidate), respectively. Intramuscular immunization of Barred Rock layers with KLH-Ent conjugate four times induced strong immune response against whole conjugate vaccine but the titer of Ent-specific IgY did not change in yolk with only a 4 fold increase detected in serum. In the second trial, three different Ent conjugate vaccines were evaluated in Rhode Island Red pullets with four subcutaneous injections. The KLH-Ent or CmeC-Ent conjugate consistently induced high level of Ent-specific IgY in both serum (up to 2,048 fold) and yolk (up to 1,024 fold) in each individual chicken. However, the Ent-specific immune response was only temporarily and moderately induced using a BSA-Ent vaccination. In the third trial, ten White Leghorn layers were subcutaneously immunized three times with KLH-Ent, leading to consistent and strong immune response against both whole conjugate and the Ent molecule in each chicken; the mean titer of Ent-specific IgY increased approximately 32 and 256 fold in serum and yolk, respectively. Consistent with its potent binding to various Ent derivatives, the Ent-specific egg yolk IgY also inhibited in vitro growth of a representative Escherichia coli strain. Together, this study demonstrated that the novel Ent conjugate vaccine could induce strong, specific, and robust immune response in chickens. The Ent-specific hyperimmune egg yolk IgY has potential for passive immune intervention against Gram-negative infections.


Assuntos
Anticorpos Antibacterianos/sangue , Vacinas Bacterianas/farmacologia , Proteínas do Ovo/imunologia , Gema de Ovo/imunologia , Enterobactina/farmacologia , Escherichia coli/efeitos dos fármacos , Imunogenicidade da Vacina , Imunoglobulinas/sangue , Animais , Vacinas Bacterianas/imunologia , Galinhas , Enterobactina/imunologia , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/imunologia , Estudos de Viabilidade , Imunização , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/farmacologia , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacologia
18.
Viruses ; 13(4)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916308

RESUMO

Mink refractory diarrhea is a seasonal disease that occurs in many mink farms in China. Mink circovirus (MiCV) has been recognized as the causative agent of the disease. The aim of the study was to develop a subunit vaccine against mink refractory diarrhea. A recombinant baculovirus strain expressing the capsid protein was constructed using the baculovirus expression vector system (BEVS). A subunit vaccine was developed based on the capsid protein with appropriate adjuvant. Then, a field trial was carried out in two districts in order to evaluate the efficiency of the subunit vaccine. The field trial indicated that in total, only 1.8% of the minks developed typical diarrhea in the vaccinated group compared with 74.5% in the control group. The vaccination could significantly reduce the infection rate of MiCV among the mink herds and could restrain the virus' shedding from feces. Furthermore, the vaccinated group had a higher average litter size in the following year compared to the control group. Collectively, the results indicated that the subunit vaccine based on the capsid protein can provide reliable protection against MiCV infection.


Assuntos
Anticorpos Antivirais/sangue , Baculoviridae/genética , Proteínas do Capsídeo/genética , Infecções por Circoviridae/prevenção & controle , Infecções por Circoviridae/veterinária , Circovirus/imunologia , Diarreia/prevenção & controle , Vison/virologia , Vacinas Virais/imunologia , Animais , Capsídeo/imunologia , Capsídeo/metabolismo , Proteínas do Capsídeo/imunologia , China , Infecções por Circoviridae/imunologia , Circovirus/genética , Diarreia/virologia , Feminino , Masculino , Vacinas de Subunidades/imunologia , Vacinas Virais/administração & dosagem
19.
Viruses ; 13(3)2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801868

RESUMO

Classical swine fever (CSF), caused by CSF virus (CSFV), is one of the most devastating viral epizootic diseases of swine in many countries. To control the disease, highly efficacious and safe live attenuated vaccines have been used for decades. However, the main drawback of these conventional vaccines is the lack of differentiability of infected from vaccinated animals (DIVA concept). Advances in biotechnology and our detailed knowledge of multiple basic science disciplines have facilitated the development of effective and safer DIVA vaccines to control CSF. To date, two types of DIVA vaccines have been developed commercially, including the subunit vaccines based on CSFV envelope glycoprotein E2 and chimeric pestivirus vaccines based on infectious cDNA clones of CSFV or bovine viral diarrhea virus (BVDV). Although inoculation of these vaccines successfully induces solid immunity against CSFV, none of them could ideally meet all demands regarding to safety, efficacy, DIVA potential, and marketability. Due to the limitations of the available choices, researchers are still striving towards the development of more advanced DIVA vaccines against CSF. This review summarizes the present status of candidate CSFV vaccines that have been developed. The strategies and approaches revealed here may also be helpful for the development of new-generation vaccines against other diseases.


Assuntos
Vírus da Febre Suína Clássica/imunologia , Peste Suína Clássica/prevenção & controle , Doenças dos Suínos/prevenção & controle , Vacinas Atenuadas/imunologia , Vacinas de Subunidades/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Peste Suína Clássica/imunologia , Gado/virologia , Vacinação em Massa , Suínos , Doenças dos Suínos/virologia , Vacinas Atenuadas/efeitos adversos , Vacinas de Subunidades/efeitos adversos , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia
20.
Viruses ; 13(5)2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925069

RESUMO

One of the most effective strategies for eliminating new and emerging infectious diseases is effective immunization. The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) warrants the need for a maximum coverage vaccine. Moreover, mutations that arise within the virus have a significant impact on the vaccination strategy. Here, we built a comprehensive in silico workflow pipeline to identify B-cell- and T-cell-stimulating antigens of SARS-CoV-2 viral proteins. Our in silico reverse vaccinology (RV) approach consisted of two parts: (1) analysis of the selected viral proteins based on annotated cellular location, antigenicity, allele coverage, epitope density, and mutation density and (2) analysis of the various aspects of the epitopes, including antigenicity, allele coverage, IFN-γ induction, toxicity, host homology, and site mutational density. After performing a mutation analysis based on the contemporary mutational amino acid substitutions observed in the viral variants, 13 potential epitopes were selected as subunit vaccine candidates. Despite mutational amino acid substitutions, most epitope sequences were predicted to retain immunogenicity without toxicity and host homology. Our RV approach using an in silico pipeline may potentially reduce the time required for effective vaccine development and can be applicable for vaccine development for other pathogenic diseases as well.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Antígenos Virais/química , Antígenos Virais/imunologia , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Humanos , Imunogenicidade da Vacina , Simulação de Acoplamento Molecular , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de Subunidades/imunologia , Vacinologia/métodos , Proteínas Virais/genética , Proteínas Virais/imunologia
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