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1.
Viruses ; 14(10)2022 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-36298792

RESUMO

Human rhinoviruses (HRVs) are small non-enveloped RNA viruses that belong to the Enterovirus genus within the Picornaviridae family and are known for causing the common cold. Though symptoms are generally mild in healthy individuals, the economic burden associated with HRV infection is significant. A vaccine could prevent disease. The Vero-cell-based viral vaccine platform technology was considered for such vaccine development. Unfortunately, most HRV strains are unable to propagate on Vero cells due to a lack of the major receptor of HRV group A and B, intercellular adhesion molecule (ICAM1, also known as CD54). Therefore, stable human ICAM1 expressing Vero cell clones were generated by transfecting the ICAM1 gene in Vero cells and selecting clones that overexpressed ICAM1 on the cell surface. Cell banks were made and expression of ICAM1 was stable for at least 30 passages. The Vero_ICAM1 cells and parental Vero cells were infected with four HRV prototypes, B14, A16, B37 and A57. Replication of all four viruses was detected in Vero_ICAM1, but not in the parental Vero cells. Altogether, Vero cells expressing ICAM1 could efficiently propagate the tested HRV strains. Therefore, ICAM1-expressing cells could be a useful tool for the development and future production of polyvalent HRV vaccines or other viruses that use ICAM1 as a receptor.


Assuntos
Molécula 1 de Adesão Intercelular , Infecções por Picornaviridae , Rhinovirus , Células Vero , Vacinas Virais , Animais , Humanos , Chlorocebus aethiops , Enterovirus/genética , Enterovirus/imunologia , Infecções por Enterovirus/genética , Infecções por Enterovirus/imunologia , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Infecções por Picornaviridae/genética , Infecções por Picornaviridae/imunologia , Rhinovirus/genética , Rhinovirus/imunologia , Células Vero/imunologia , Vacinas Virais/imunologia
2.
Arch. prev. riesgos labor. (Ed. impr.) ; 25(4): 358-378, oct. 2022.
Artigo em Espanhol | IBECS | ID: ibc-212762

RESUMO

Introducción: El objetivo fue estimar la evolución de los niveles de anticuerpos anti-SARS-CoV-2 y los factores asociados, así como la incidencia de nuevas infecciones en el periodo de seguimiento.Método: Estudio de cohorte prospectivo de una muestra representativa de trabajadores del Hospital General Universitario de Castellón a los 8 meses de recibir la 2ª dosis de la vacuna Pfizer-BioNTech contra el SARS-CoV-2, mediante la determinación de anticuerpos IgG-S y IgG-NP, y la cumplimentación de un cuestionario. Se compararon los resultados con los del inicio de la cohorte en febrero de 2021. Se usó regresión lineal múltiple y regresión de Poisson. Resultados: Participaron 253 trabajadores de los 275 reclutados al inicio de la cohorte (92%). Todos mantenían niveles detectables de IgG-S, mediana de 691,5 UA/ml, disminu-yendo un 93,3% con respecto al inicio. Los descensos de IgG-S fueron mayores con la edad y la obesidad, y menores en aquellos con historia de COVID-19, IgG-S elevada inicial, prac-ticar ejercicio habitual y ser fumador. Tener IgG-NP se asoció positivamente con historia de COVID-19, tomar vitamina D, y disminuyó del 4,4% al 1,2%. Se produjeron 4 casos de COVID-19 en la cohorte, con una tasa de incidencia del 1,7%, con un fallecimiento en un participante con tratamiento inmunosupresor, solo un caso fue asintomático y no hubo reinfecciones. Conclusiones: Se produce un descenso general de los anticuerpos IgG-S e IgG-NP después de la segunda dosis de vacuna Pfizer-BioNTech, así como nuevas infecciones por SARS-CoV-2. Se recomienda dosis de recuerdo, mantener medidas protectoras y determinar el umbral de anticuerpos protectores de la vacunación (AU)


Introduction: The aim was to estimate the evolution of the levels of anti-SARS-CoV-2 an-tibodies, the associated factors, and the incidence of new infections during the follow-up period. Method: Prospective cohort study of a representative sample of workers at the General Uni-versity Hospital of Castellon 8 months after receiving the second dose of Pfizer-BioNTech vaccine against SARS-CoV-2, by determining IgG-S, IgG-NP, follow-up and response to a questionnaire. The results were compared with those at the start of the cohort in February 2021. Multivariate linear regression and Poisson regression were used. Results: A total of 253 workers participated out of the 275 in the start of the cohort. All had detectable levels of IgG-S, median 691% AU/ml, decreasing by 93.3% compared with the first study. The decline of IgG-S increased with age and obesity; and decreased with a COVID-19 previous history, regular exercise, and in smokers. IgG-NP was positively associ-ated with a history of COVID-19, taking vitamin D, and decreased from 4.4% to 1.2%. There were 4 new cases of COVID-19 in the cohort, with and incidence rate of 1.7%. One death occurred in a participant with immunosuppressive treatment, only one case was asymp-tomatic and no reinfections occurred Conclusions: A general decrease of IgG-S and IgG-NP antibodies after the second dose of Pfizer-BioNTech vaccine was observed in the cohort, as well as with new SARS-CoV-2 in-fections. Booster doses, maintaining protective measures and further determination of the protection threshold of vaccination are recommended (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Hospitais Gerais , Recursos Humanos em Hospital , Anticorpos Antivirais/sangue , Vacinas Virais/imunologia , Infecções por Coronavirus/prevenção & controle , Estudos Prospectivos , Estudos de Coortes , Imunoglobulina G/imunologia , Anticorpos Antivirais/imunologia
3.
Proc Natl Acad Sci U S A ; 119(35): e2110105119, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35994646

RESUMO

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main target for neutralizing antibodies (NAbs). The S protein trimer is anchored in the virion membrane in its prefusion (preS) but metastable form. The preS protein has been stabilized by introducing two or six proline substitutions, to generate stabilized, soluble 2P or HexaPro (6P) preS proteins. Currently, it is not known which form is the most immunogenic. Here, we generated recombinant vesicular stomatitis virus (rVSV) expressing preS-2P, preS-HexaPro, and native full-length S, and compared their immunogenicity in mice and hamsters. The rVSV-preS-HexaPro produced and secreted significantly more preS protein compared to rVSV-preS-2P. Importantly, rVSV-preS-HexaPro triggered significantly more preS-specific serum IgG antibody than rVSV-preS-2P in both mice and hamsters. Antibodies induced by preS-HexaPro neutralized the B.1.1.7, B.1.351, P.1, B.1.427, and B.1.617.2 variants approximately two to four times better than those induced by preS-2P. Furthermore, preS-HexaPro induced a more robust Th1-biased cellular immune response than preS-2P. A single dose (104 pfu) immunization with rVSV-preS-HexaPro and rVSV-preS-2P provided complete protection against challenge with mouse-adapted SARS-CoV-2 and B.1.617.2 variant, whereas rVSV-S only conferred partial protection. When the immunization dose was lowered to 103 pfu, rVSV-preS-HexaPro induced two- to sixfold higher antibody responses than rVSV-preS-2P in hamsters. In addition, rVSV-preS-HexaPro conferred 70% protection against lung infection whereas only 30% protection was observed in the rVSV-preS-2P. Collectively, our data demonstrate that both preS-2P and preS-HexaPro are highly efficacious but preS-HexaPro is more immunogenic and protective, highlighting the advantages of using preS-HexaPro in the next generation of SARS-CoV-2 vaccines.


Assuntos
Prolina , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Desenvolvimento de Vacinas , Estomatite Vesicular , Vacinas Virais , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/genética , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Cricetinae , Humanos , Camundongos , Prolina/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Estomatite Vesicular/imunologia , Estomatite Vesicular/prevenção & controle , Estomatite Vesicular/virologia , Vesiculovirus/imunologia , Proteínas Virais/imunologia , Vacinas Virais/imunologia
4.
JCI Insight ; 7(18)2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-35972807

RESUMO

Lentiviral vector-based dendritic cell vaccines induce protective T cell responses against viral infection and cancer in animal models. In this study, we tested whether preventative and therapeutic vaccination could be achieved by direct injection of antigen-expressing lentiviral vector, obviating the need for ex vivo transduction of dendritic cells. Injected lentiviral vector preferentially transduced splenic dendritic cells and resulted in long-term expression. Injection of a lentiviral vector encoding an MHC class I-restricted T cell epitope of lymphocytic choriomeningitis virus (LCMV) and CD40 ligand induced an antigen-specific cytolytic CD8+ T lymphocyte response that protected the mice from infection. The injection of chronically infected mice with a lentiviral vector encoding LCMV MHC class I and II T cell epitopes and a soluble programmed cell death 1 microbody rapidly cleared the virus. Vaccination by direct injection of lentiviral vector was more effective in sterile alpha motif and HD-domain containing protein 1-knockout (SAMHD1-knockout) mice, suggesting that lentiviral vectors containing Vpx, a lentiviral protein that increases the efficiency of dendritic cell transduction by inducing the degradation of SAMHD1, would be an effective strategy for the treatment of chronic disease in humans.


Assuntos
Vacinas Virais , Viroses , Animais , Ligante de CD40 , Epitopos de Linfócito T , Vetores Genéticos , Lentivirus , Vírus da Coriomeningite Linfocítica , Camundongos , Proteína 1 com Domínio SAM e Domínio HD , Vacinas Virais/imunologia
5.
J Virol ; 96(13): e0014322, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35658531

RESUMO

Differentiation of infected from vaccinated hosts (DIVH) is a critical step in virus eradication programs. DIVH-compatible vaccines, however, take years to develop, and are therefore unavailable for fighting the sudden outbreaks that typically drive pandemics. Here, we establish a protocol for the swift and efficient development of DIVH assays, and show that this approach is compatible with any type of vaccines. Using porcine circovirus 2 (PCV2) as the experimental model, the first step is to use Immunoglobin G (IgG) sero-dynamics (IsD) curves to aid epitope discovery (IsDAED): PCV2 Cap peptides were categorized into three types: null interaction, nonspecific interaction (NSI), and specific interaction (SI). We subsequently compared IsDAED approach and traditional approach, and demonstrated identifying SI peptides and excluding NSI peptides supports efficient diagnostic kit development, specifically using a protein-peptide hybrid microarray (PPHM). IsDAED directed the design of a DIVH protocol for three types of PCV2 vaccines (while using a single PPHM). Finally, the DIVH protocol successfully differentiated infected pigs from vaccinated pigs at five farms. This IsDAED approach is almost certainly extendable to other viruses and host species. IMPORTANCE Sudden outbreaks of pandemics caused by virus, such as SARS-CoV-2, has been determined as a public health emergency of international concern. However, the development of a DIVH-compatible vaccine is time-consuming and full of uncertainty, which is unsuitable for an emergent situation like the ongoing COVID-19 pandemic. Along with the development and public health implementation of new vaccines to prevent human diseases, e.g., human papillomavirus vaccines for cervical cancer; enterovirus 71 vaccines for hand, foot, and mouth disease; and most recently SARS-CoV-2, there is an increasing demand for DIVH. Here, we use the IsDAED approach to confirm SI peptides and to exclude NSI peptides, finally to direct the design of a DIVH protocol. It is plausible that our IsDAED approach is applicable for other infectious disease.


Assuntos
Anticorpos Antivirais , Infecções por Circoviridae , Epitopos , Imunoglobulina G , Vacinas Virais , Animais , Anticorpos Antivirais/sangue , COVID-19 , Infecções por Circoviridae/imunologia , Circovirus , Modelos Animais de Doenças , Epitopos/análise , Epitopos/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Peptídeos , SARS-CoV-2 , Suínos , Doenças dos Suínos/imunologia , Vacinas Virais/imunologia
7.
Curr Opin Immunol ; 77: 102209, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35598506

RESUMO

Viral proteins fold into a variety of structures as they perform their functions. Structure-based vaccine design aims to exploit knowledge of an antigen's architecture to stabilize it in a vulnerable conformation. We summarize the general principles of structure-based vaccine design, with a focus on the major types of sequence modifications: proline, disulfide, cavity-filling, electrostatic and hydrogen-bond substitution, as well as domain deletion. We then review recent applications of these principles to vaccine-design efforts across five viral families: Coronaviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, and Filoviridae. Outstanding challenges include continued application of proven design principles to pathogens of interest, as well as development of new strategies for those pathogens that resist traditional techniques.


Assuntos
Desenvolvimento de Vacinas , Proteínas Virais , Vacinas Virais , Coronaviridae , Filoviridae , Humanos , Orthomyxoviridae , Paramyxoviridae , Pneumovirinae , Proteínas Virais/imunologia , Vacinas Virais/imunologia
8.
Front Immunol ; 13: 832264, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35558083

RESUMO

African swine fever (ASF) is among the most devastating viral diseases of pigs and wild boar worldwide. In recent years, the disease has spread alarmingly. Despite intensive research activities, a commercialized vaccine is still not available, and efficacious live attenuated vaccine candidates raise safety concerns. From a safety perspective, inactivated preparations would be most favourable. However, both historical and more recent trials with chemical inactivation did not show an appreciable protective effect. Under the assumption that the integrity of viral particles could enhance presentation of antigens, we used gamma irradiation for inactivation. To this means, gamma irradiated ASFV "Estonia 2014" was adjuvanted with either Polygen™ or Montanide™ ISA 201 VG, respectively. Subsequently, five weaner pigs per preparation were immunized twice with a three-week interval. Six weeks after the first immunization, all animals were challenged with the highly virulent ASFV strain "Armenia 2008". Although ASFV p72-specific IgG antibodies were detectable in all vaccinated animals prior challenge, no protection could be observed. All animals developed an acute lethal course of ASF and had to be euthanized at a moderate humane endpoint within six days. Indeed, the vaccinated pigs showed even higher clinical scores and a higher inner body temperature than the control group. However, significantly lower viral loads were detectable in spleen and liver of immunized animals at the time point of euthanasia. This phenomenon suggests an immune mediated disease enhancement that needs further investigation.


Assuntos
Febre Suína Africana , Vacinas Virais , Febre Suína Africana/prevenção & controle , Vírus da Febre Suína Africana , Animais , Raios gama , Imunogenicidade da Vacina , Suínos , Vacinação , Vacinas Atenuadas/imunologia , Proteínas Virais , Vacinas Virais/imunologia
9.
N Engl J Med ; 386(23): 2201-2212, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35613036

RESUMO

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides natural immunity against reinfection. Recent studies have shown waning of the immunity provided by the BNT162b2 vaccine. The time course of natural and hybrid immunity is unknown. METHODS: Using the Israeli Ministry of Health database, we extracted data for August and September 2021, when the B.1.617.2 (delta) variant was predominant, on all persons who had been previously infected with SARS-CoV-2 or who had received coronavirus 2019 vaccine. We used Poisson regression with adjustment for confounding factors to compare the rates of infection as a function of time since the last immunity-conferring event. RESULTS: The number of cases of SARS-CoV-2 infection per 100,000 person-days at risk (adjusted rate) increased with the time that had elapsed since vaccination with BNT162b2 or since previous infection. Among unvaccinated persons who had recovered from infection, this rate increased from 10.5 among those who had been infected 4 to less than 6 months previously to 30.2 among those who had been infected 1 year or more previously. Among persons who had received a single dose of vaccine after previous infection, the adjusted rate was low (3.7) among those who had been vaccinated less than 2 months previously but increased to 11.6 among those who had been vaccinated at least 6 months previously. Among previously uninfected persons who had received two doses of vaccine, the adjusted rate increased from 21.1 among those who had been vaccinated less than 2 months previously to 88.9 among those who had been vaccinated at least 6 months previously. CONCLUSIONS: Among persons who had been previously infected with SARS-CoV-2 (regardless of whether they had received any dose of vaccine or whether they had received one dose before or after infection), protection against reinfection decreased as the time increased since the last immunity-conferring event; however, this protection was higher than that conferred after the same time had elapsed since receipt of a second dose of vaccine among previously uninfected persons. A single dose of vaccine after infection reinforced protection against reinfection.


Assuntos
COVID-19 , Vacina BNT162/imunologia , Vacina BNT162/uso terapêutico , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Humanos , Imunidade Inata , Reinfecção/imunologia , Reinfecção/prevenção & controle , SARS-CoV-2 , Fatores de Tempo , Vacinas Virais/imunologia , Vacinas Virais/uso terapêutico
10.
Virol Sin ; 37(2): 266-276, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35527225

RESUMO

Arthropod-borne chikungunya virus (CHIKV) infection can cause a debilitating arthritic disease in human. However, there are no specific antiviral drugs and effective licensed vaccines against CHIKV available for clinical use. Here, we developed an mRNA-lipid nanoparticle (mRNA-LNP) vaccine expressing CHIKV E2-E1 antigen, and compared its immunogenicity with soluble recombinant protein sE2-E1 antigen expressed in S2 cells. For comparison, we first showed that recombinant protein antigens mixed with aluminum adjuvant elicit strong antigen-specific humoral immune response and a moderate cellular immune response in C57BL/6 mice. Moreover, sE2-E1 vaccine stimulated 12-23 folds more neutralizing antibodies than sE1 vaccine and sE2 vaccine. Significantly, when E2-E1 gene was delivered by an mRNA-LNP vaccine, not only the better magnitude of neutralizing antibody responses was induced, but also greater cellular immune responses were generated, especially for CD8+ T cell responses. Moreover, E2-E1-LNP induced CD8+ T cells can perform cytotoxic effect in vivo. Considering its better immunogenicity and convenience of preparation, we suggest that more attention should be placed to develop CHIKV E2-E1-LNP mRNA vaccine.


Assuntos
Formação de Anticorpos , Febre de Chikungunya , Imunidade Celular , Vacinas Virais , Vacinas de mRNA , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos T CD8-Positivos/imunologia , Febre de Chikungunya/imunologia , Febre de Chikungunya/prevenção & controle , Vírus Chikungunya , Lipossomos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Vacinas Sintéticas/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/imunologia , Vacinas de mRNA/imunologia
11.
J Virol ; 96(9): e0006422, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35416719

RESUMO

Alphaviruses infect cells by a low pH-dependent fusion reaction between viral and host cell membranes that is mediated by the viral E1 glycoprotein. Most reported alphavirus E1 sequences include two phenylalanines (F87 and F95) in the fusion loop, yet the role of these residues in viral infectivity remains to be defined. Following introduction of wild type (WT), E1-F87A, and E1-F95A chikungunya virus (CHIKV) RNA genomes into cells, viral particle production was similar in magnitude. However, CHIKV E1-F87A and E1-F95A virions displayed impaired infectivity compared with WT CHIKV particles. Although WT, E1-F87A, and E1-F95A particles bound cells with similar efficiencies, E1-F87A and E1-F95A particles were unable to undergo fusion and entry into cells. Introduction of an F95A mutation in the E1 fusion loop of Mayaro virus or Venezuelan equine encephalitis virus also resulted in poorly infectious virions. We further tested whether an E1-F87A or E1-F95A mutation could be incorporated into a live-attenuated vaccine strain, CHIKV 181/25, to enhance vaccine safety. Infection of immunocompromised Ifnar1-/- and Irf3-/-Irf5-/-Irf7-/- mice with 181/25E1-F87A or 181/25E1-F95A resulted in 0% mortality, compared with 100% mortality following 181/25 infection. Despite this enhanced attenuation, surviving Ifnar1-/- and Irf3-/-Irf5-/-Irf7-/- mice were protected against virulent virus re-challenge. Moreover, single-dose immunization of WT mice with either 181/25, 181/25E1-F87A, or 181/25E1-F95A elicited CHIKV-specific antibody responses and protected against pathogenic CHIKV challenge. These studies define a critical function for residues E1-F87 and E1-F95 in alphavirus fusion and entry into target cells and suggest that incorporation of these mutations could enhance the safety of live-attenuated alphavirus vaccine candidates. IMPORTANCE Alphaviruses are human pathogens that cause both debilitating acute and chronic musculoskeletal disease and potentially fatal encephalitis. In this study, we determined that two highly conserved phenylalanine residues in the alphavirus E1 glycoprotein are required for fusion of viral and host cell membranes and viral entry into target cells. We further demonstrated that mutation of these phenylalanines results in a substantial loss of viral virulence but not immunogenicity. These data enhance an understanding of the viral determinants of alphavirus entry into host cells and could contribute to the development of new antivirals targeting these conserved phenylalanines or new live-attenuated alphavirus vaccines.


Assuntos
Febre de Chikungunya , Vírus Chikungunya , Proteínas do Envelope Viral , Vacinas Virais , Animais , Anticorpos Antivirais , Febre de Chikungunya/virologia , Vírus Chikungunya/patogenicidade , Vírus Chikungunya/fisiologia , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Knockout , Fenilalanina/química , Domínios Proteicos , Vacinas Atenuadas/imunologia , Proteínas do Envelope Viral/química , Vacinas Virais/imunologia , Replicação Viral
12.
J Virol ; 96(9): e0033622, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35404082

RESUMO

Epstein-Barr virus (EBV), the first identified human tumor virus, is etiologically associated with various kinds of malignant and benign diseases, accounting for 265,000 cancer incident cases and 164,000 cancer deaths in 2017. EBV prophylactic vaccine development has been gp350 centered for several decades. However, clinical studies show that gp350-centered vaccines fail to prevent EBV infection. Advances in the EBV infection mechanisms shed light on gB and gHgL, the two key components of the infection apparatus. In this study, for the first time, we utilized recombinant vesicular stomatitis virus (VSV) to display EBV gB (VSV-ΔG-gB/gB-G) or gHgL (VSV-ΔG-gHgL). In vitro studies confirmed successful virion production and glycoprotein presentation on the virion surface. In mouse models, VSV-ΔG-gB/gB-G or VSV-ΔG-gHgL elicited potent humoral responses. Neutralizing antibodies elicited by VSV-ΔG-gB/gB-G were prone to prevent B cell infection, while those elicited by VSV-ΔG-gHgL were prone to prevent epithelial cell infection. Combinatorial vaccination yields an additive effect. The ratio of endpoint neutralizing antibody titers to the endpoint total IgG titers immunized with VSV-ΔG-gHgL was approximately 1. The ratio of IgG1/IgG2a after VSV-ΔG-gB/gB-G immunization was approximately 1 in a dose-dependent, adjuvant-independent manner. Taken together, VSV-based EBV vaccines can elicit a high ratio of epithelial and B lymphocyte neutralizing antibodies, implying their unique potential as EBV prophylactic vaccine candidates. IMPORTANCE Epstein-Barr virus (EBV), one of the most common human viruses and the first identified human oncogenic virus, accounted for 265,000 cancer incident cases and 164,000 cancer deaths in 2017 as well as millions of nonmalignant disease cases. So far, no prophylactic vaccine is available to prevent EBV infection. In this study, for the first time, we reported the VSV-based EBV vaccines presenting two key components of the EBV infection apparatus, gB and gHgL. We confirmed potent antigen-specific antibody generation; these antibodies prevented EBV from infecting epithelial cells and B cells, and the IgG1/IgG2a ratio indicated balanced humoral-cellular responses. Taken together, we suggest VSV-based EBV vaccines are potent prophylactic candidates for clinical studies and help eradicate numerous EBV-associated malignant and benign diseases.


Assuntos
Infecções por Vírus Epstein-Barr , Vesiculovirus , Vacinas Virais , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Infecções por Vírus Epstein-Barr/prevenção & controle , Herpesvirus Humano 4/fisiologia , Imunidade Humoral , Imunoglobulina G/sangue , Camundongos , Vesiculovirus/genética , Vacinas Virais/imunologia
13.
Vet Microbiol ; 268: 109415, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35395543

RESUMO

Bovine parainfluenza virus type 3 (BPIV3) is one of the most important viral respiratory pathogens of cattle. No specific therapies are available for BPIV3 infection; vaccination is one of the most effective ways to prevent BPIV3 infection. We therefore prepared the self-assembled BPIV3 nanoparticles by genetically fusing the ectodomain of BPIV3 haemagglutinin-neuraminidase (HN) (HNex) to the NH2 terminus of ferritin (HNex-RFNp) using a baculovirus expression system. It was found that HNex-RFNp-induced bone marrow-derived dendritic cell (BMDC) maturation through the upregulated expression of surface molecules (MHC II, CD80, CD86, and CD40), increased the secretion of inflammatory cytokines (IL-6, IL-12, TNF-α, and IFN-γ), and reduced antigen phagocytosis and T cell activation capacity. HNex-RFNp positively regulated IκBα and NF-κB (p65) phosphorylation and facilitated NF-κB (p65) translocation into the nuclei of mature BMDCs. Incubating RFNp-treated BMDCs with TLR4 and NF-κB (p65) inhibitors, suppressed surface molecule expression as well as pro-inflammatory cytokine production and IκBα and NF-κB (p65) activities. The BPIV3 HNex protein induced BMDC maturation to some extent but was significantly weaker than HNex-RFNp. We found that HNex-RFNp induced a higher titre of specific antibodie, haemagglutinin inhibition (HI) antibody, and virus neutralisation (VN) antibody, and a comprehensive cellular immune response. We examined protection against BPIV3 challenge in a mouse model. Pathological changes were not observed in the lungs of HNex-RFNp-vaccinated mice. Levels of BPIV3 RNA and virus titres in the lungs and trachea were significantly lower in the HNex-RFNp, than HNex, inactivated BPIV3, and PBS groups. In summary, HNex-RFNp elicited better immunogenicity than HNex or inactivated BPIV3 and could be developed as an effective vaccine to protect against BPIV3 infection.


Assuntos
Células Dendríticas , NF-kappa B , Nanopartículas , Vírus da Parainfluenza 3 Bovina , Vacinas Virais , Viroses , Animais , Bovinos , Células Dendríticas/imunologia , Hemaglutininas/metabolismo , Imunogenicidade da Vacina , Ativação Linfocitária , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Vacinas Virais/imunologia , Viroses/prevenção & controle , Viroses/veterinária
16.
J Virol ; 96(8): e0020922, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35343792

RESUMO

Several highly pathogenic mammarenaviruses cause severe hemorrhagic and neurologic disease in humans for which vaccines and antivirals are limited or unavailable. New World (NW) mammarenavirus Machupo virus (MACV) infection causes Bolivian hemorrhagic fever in humans. We previously reported that the disruption of specific N-linked glycan sites on the glycoprotein (GPC) partially attenuates MACV in an interferon alpha/beta and gamma (IFN-α/ß and -γ) receptor knockout (R-/-) mouse model. However, some capability to induce neurological pathology still remained. The highly pathogenic Junin virus (JUNV) is another NW arenavirus closely related to MACV. An F427I substitution in the GPC transmembrane domain (TMD) rendered JUNV attenuated in a lethal mouse model after intracranial inoculation. In this study, we rationally designed and rescued a MACV containing mutations at two glycosylation sites and the corresponding F438I substitution in the GPC TMD. The MACV mutant is fully attenuated in IFN-α/ß and -γ R-/- mice and outbred guinea pigs. Furthermore, inoculation with this mutant MACV completely protected guinea pigs from wild-type MACV lethal challenge. Last, we found the GPC TMD F438I substitution greatly impaired MACV growth in neuronal cell lines of mouse and human origins. Our results highlight the critical roles of the glycans and the TMD on the GPC in arenavirus virulence, which provide insight into the rational design of potential vaccine candidates for highly pathogenic arenaviruses. IMPORTANCE For arenaviruses, the only vaccine available is the live attenuated Candid#1 vaccine, a JUNV vaccine approved in Argentina. We and others have found that the glycans on GPC and the F427 residue in the GPC TMD are important for virulence of JUNV. Nevertheless, mutating either of them is not sufficient for full and stable attenuation of JUNV. Using reverse genetics, we disrupted specific glycosylation sites on MACV GPC and also introduced the corresponding F438I substitution in the GPC TMD. This MACV mutant is fully attenuated in two animal models and protects animals from lethal infection. Thus, our studies highlight the feasibility of rational attenuation of highly pathogenic arenaviruses for vaccine development. Another important finding from this study is that the F438I substitution in GPC TMD could substantially affect MACV replication in neurons. Future studies are warranted to elucidate the underlying mechanism and the implication of this mutation in arenavirus neural tropism.


Assuntos
Arenavirus do Novo Mundo , Febre Hemorrágica Americana , Vacinas Virais , Animais , Arenavirus do Novo Mundo/genética , Arenavirus do Novo Mundo/imunologia , Modelos Animais de Doenças , Glicoproteínas/metabolismo , Glicosilação , Cobaias , Febre Hemorrágica Americana/imunologia , Febre Hemorrágica Americana/virologia , Vírus Junin/genética , Vírus Junin/imunologia , Mutação , Vacinas Atenuadas/imunologia , Vacinas Virais/imunologia
17.
Science ; 375(6585): 1133-1139, 2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-35271333

RESUMO

The vaccine and drug discovery responses to COVID-19 have worked far better than could have been imagined. Yet by the end of 2021, more than 5 million people had died, and the pandemic continues to evolve and rage globally. This Review will describe how each of the vaccines, antibody therapies, and antiviral drugs that have been approved to date were built on decades of investment in technology and basic science. We will caution that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has so far proven a straightforward test of our pandemic preparedness, and we will recommend steps we should undertake now to prepare for, to minimize the effects of, and ideally to prevent future pandemics. Other Reviews in this series describe the interactions of SARS-CoV-2 with the immune system and those therapies that target the host response to infection.


Assuntos
Antivirais/uso terapêutico , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Anticorpos Monoclonais/uso terapêutico , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Progressão da Doença , Desenvolvimento de Medicamentos , Descoberta de Drogas , Humanos , SARS-CoV-2/efeitos dos fármacos , Desenvolvimento de Vacinas , Vacinologia , Vacinas Virais/imunologia , Viroses/tratamento farmacológico , Viroses/prevenção & controle
18.
Proc Natl Acad Sci U S A ; 119(14): e2119093119, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35312341

RESUMO

SignificanceUsing SARS-CoV-2 as a relevant case study for infectious disease, we investigate the structure-function relationships that dictate antiviral spherical nucleic acid (SNA) vaccine efficacy. We show that the SNA architecture can be rapidly employed to target COVID-19 through incorporation of the receptor-binding domain, and that the resulting vaccine potently activates human cells in vitro and mice in vivo. Furthermore, when challenged with a lethal viral infection, only mice treated with the SNA vaccine survived. Taken together, this work underscores the importance of rational vaccine design for infectious disease to yield vaccines that elicit more potent immune responses to effectively fight disease.


Assuntos
Controle de Doenças Transmissíveis , Ácidos Nucleicos/imunologia , Vacinas de DNA/imunologia , Animais , Biotecnologia , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis/métodos , Doenças Transmissíveis/etiologia , Doenças Transmissíveis/imunologia , Humanos , Ácidos Nucleicos/química , SARS-CoV-2/imunologia , Desenvolvimento de Vacinas , Vacinas de DNA/genética , Vacinas Virais/genética , Vacinas Virais/imunologia
19.
Med Sci Monit ; 28: e935879, 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35313326

RESUMO

According to world statistics, men are more susceptible to the coronavirus disease 2019 (COVID-19) than are women. Considering the interconnection between infections and male infertility, investigation of the potential impact of COVID-19 on men's reproductive health is now a particularly relevant topic. Published data indicate decreased sperm quality and orchitis development in patients with COVID-19, including reduced sperm count, decreased sperm motility, and elevated DNA fragmentation index. Although mass vaccination against COVID-19 is currently being carried out worldwide using available authorized vaccines, the effect of these vaccines on men's reproductive health has not yet been investigated. There is currently no evidence that SARS-CoV-2 can be transmitted in semen, but available data suggest that it can infect spermatogonia, spermatids, Leydig cells, and Sertoli cells. Therefore, SARS-CoV-2 orchitis and reduced male fertility may be long-term complications of COVID-19, which requires further investigation. Currently, there is also no evidence that vaccines against SARS-CoV-2 have any pathological effects on spermatogenesis or male reproductive health. Thus, further studies are needed to determine the effects of COVID-19 and COVID-19 vaccines on men's reproductive health, which will help to optimize the management and rehabilitation of these patients. This review aims to discuss recent studies on the impact of the COVID-19 and COVID-19 vaccines on men's reproductive health. The article addresses various issues such as the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on testosterone biosynthesis, semen parameters, testicular tissue, and epididymis.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/imunologia , Motilidade Espermática/efeitos dos fármacos , Vacinas contra COVID-19/imunologia , Humanos , Masculino , Saúde Reprodutiva/tendências , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Motilidade Espermática/fisiologia , Vacinas Virais/imunologia
20.
Proc Natl Acad Sci U S A ; 119(12): e2200065119, 2022 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-35286211

RESUMO

SignificanceConcern has increased about the pandemic potential of Nipah virus (NiV). Similar to SARS-CoV-2, NiV is an RNA virus that is transmitted by respiratory droplets. There are currently no NiV vaccines licensed for human use. While several preventive vaccines have shown promise in protecting animals against lethal NiV disease, most studies have assessed protection 1 mo after vaccination. However, in order to contain and control outbreaks, vaccines that can rapidly confer protection in days rather than months are needed. Here, we show that a recombinant vesicular stomatitis virus vector expressing the NiV glycoprotein can completely protect monkeys vaccinated 7 d prior to NiV exposure and 67% of animals vaccinated 3 d before NiV challenge.


Assuntos
Infecções por Henipavirus/veterinária , Vírus Nipah/imunologia , Doenças dos Primatas/prevenção & controle , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais/imunologia , Biomarcadores , Vetores Genéticos , Estimativa de Kaplan-Meier , Testes de Neutralização , Avaliação de Resultados em Cuidados de Saúde , Doenças dos Primatas/diagnóstico , Doenças dos Primatas/mortalidade , Doenças dos Primatas/virologia , Vacinação , Carga Viral
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