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1.
N Engl J Med ; 381(20): 1897-1908, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31722150

RESUMO

BACKGROUND: Many countries have stockpiled vaccines because of concerns about the reemergence of smallpox. Traditional smallpox vaccines are based on replicating vaccinia viruses; these vaccines have considerable side effects. METHODS: To evaluate the efficacy of modified vaccinia Ankara (MVA) as a potential smallpox vaccine, we randomly assigned 440 participants to receive two doses of MVA followed by one dose of the established replicating-vaccinia vaccine ACAM2000 (the MVA group) or to receive one dose of ACAM2000 (the ACAM2000-only group). The two primary end points were noninferiority of the MVA vaccine to ACAM2000 with respect to the peak serum neutralizing antibody titers and attenuation of the ACAM2000-associated major cutaneous reaction by previous MVA vaccination, measured according to the maximum lesion area and the derived area attenuation ratio. RESULTS: A total of 220 and 213 participants were randomly assigned and vaccinated in the MVA group and ACAM2000-only group, respectively, and 208 participants received two MVA vaccinations. At peak visits, MVA vaccination induced a geometric mean titer of neutralizing antibodies of 153.5 at week 6, as compared with 79.3 at week 4 with ACAM2000 (a ratio of 1.94 [95% confidence interval {CI}, 1.56 to 2.40]). At day 14, the geometric mean titer of neutralizing antibodies induced by a single MVA vaccination (16.2) was equal to that induced by ACAM2000 (16.2), and the percentages of participants with seroconversion were similar (90.8% and 91.8%, respectively). The median lesion areas of the major cutaneous reaction were 0 mm2 in the MVA group and 76.0 mm2 in the ACAM2000-only group, resulting in an area attenuation ratio of 97.9% (95% CI, 96.6 to 98.3). There were fewer adverse events or adverse events of grade 3 or higher after both MVA vaccination periods in the MVA group than in the ACAM2000-only group (17 vs. 64 participants with adverse events of grade 3 or higher, P<0.001). CONCLUSIONS: No safety concerns associated with the MVA vaccine were identified. Immune responses and attenuation of the major cutaneous reaction suggest that this MVA vaccine protected against variola infection. (Funded by the Office of the Assistant Secretary for Preparedness and Response Biomedical Advanced Research and Development Authority of the Department of Health and Human Services and Bavarian Nordic; ClinicalTrials.gov number, NCT01913353.).


Assuntos
Anticorpos Antivirais/sangue , Vacina Antivariólica/imunologia , Varíola/prevenção & controle , Vírus Vaccinia/imunologia , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Feminino , Humanos , Masculino , Varíola/imunologia , Vacina Antivariólica/efeitos adversos , Resultado do Tratamento , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Adulto Jovem
2.
Infect Immun ; 88(1)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31591165

RESUMO

Despite the great increase in the understanding of the biology and pathogenesis of Mycobacterium tuberculosis achieved by the scientific community in recent decades, tuberculosis (TB) still represents one of the major threats to global human health. The only available vaccine (Mycobacterium bovis BCG) protects children from disseminated forms of TB but does not effectively protect adults from the respiratory form of the disease, making the development of new and more-efficacious vaccines against the pulmonary forms of TB a major goal for the improvement of global health. Among the different strategies being developed to reach this goal is the construction of attenuated strains more efficacious and safer than BCG. We recently showed that a sigE mutant of M. tuberculosis was more attenuated and more efficacious than BCG in a mouse model of infection. In this paper, we describe the construction and characterization of an M. tuberculosis sigE fadD26 unmarked double mutant fulfilling the criteria of the Geneva Consensus for entering human clinical trials. The data presented suggest that this mutant is even more attenuated and slightly more efficacious than the previous sigE mutant in different mouse models of infection and is equivalent to BCG in a guinea pig model of infection.


Assuntos
Ligases/deficiência , Mycobacterium tuberculosis/imunologia , Fator sigma/deficiência , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/prevenção & controle , Animais , Proteínas de Bactérias , Modelos Animais de Doenças , Cobaias , Camundongos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/genética , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Virulência
3.
Nat Commun ; 10(1): 4595, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597913

RESUMO

N6-methyladenosine (m6A) is the most prevalent internal modification of mRNAs in most eukaryotes. Here we show that RNAs of human respiratory syncytial virus (RSV) are modified by m6A within discreet regions and that these modifications enhance viral replication and pathogenesis. Knockdown of m6A methyltransferases decreases RSV replication and gene expression whereas knockdown of m6A demethylases has the opposite effect. The G gene transcript contains the most m6A modifications. Recombinant RSV variants expressing G transcripts that lack particular clusters of m6A display reduced replication in A549 cells, primary well differentiated human airway epithelial cultures, and respiratory tracts of cotton rats. One of the m6A-deficient variants is highly attenuated yet retains high immunogenicity in cotton rats. Collectively, our results demonstrate that viral m6A methylation upregulates RSV replication and pathogenesis and identify viral m6A methylation as a target for rational design of live attenuated vaccine candidates for RSV and perhaps other pneumoviruses.


Assuntos
Adenosina/análogos & derivados , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Replicação Viral/imunologia , Células A549 , Adenosina/genética , Adenosina/imunologia , Adenosina/metabolismo , Animais , Anticorpos Antivirais/imunologia , Feminino , Células HeLa , Humanos , Masculino , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/patogenicidade , Sigmodontinae , Regulação para Cima/imunologia , Vacinas Atenuadas/imunologia , Células Vero , Virulência/genética , Virulência/imunologia , Replicação Viral/genética
4.
Arch Virol ; 164(12): 2931-2941, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31538254

RESUMO

Lumpy skin disease virus (LSDV) infections can cause massive clinical signs in cattle and have great economic impact due to severe trade restrictions. For LSDV control, only live attenuated vaccines are commercially available, but they currently are not authorized in the European Union. Moreover, these vaccine virus strains can induce substantial side effects with clinical signs similar to infections with virulent LSDV. In our study, we compared clinical symptoms, viremia, and seroconversion of cattle inoculated either with a virulent field strain from North Macedonia isolated from diseased cattle in 2016 or with the attenuated LSDV vaccine strain "Neethling". Using specimens from the field and from experimental inoculation, different diagnostic tools, including a pan-capripox real-time qPCR, newly developed duplex real-time qPCR assays for differentiation between virulent and attenuated LSDV strains, and several serological methods (ELISA, indirect immunofluorescence test and serum neutralization test [SNT]) were evaluated. Our data show a high analytical sensitivity of both tested duplex real-time qPCR systems for the reliable distinction of LSDV field and vaccine strains. Moreover, the commercially available capripox double-antigen ELISA seems to be as specific as the SNT and therefore provides an excellent tool for rapid and simple serological examination of LSDV-vaccinated or infected cattle.


Assuntos
Doença Nodular Cutânea/diagnóstico , Vírus da Doença Nodular Cutânea/classificação , Vacinas Atenuadas/classificação , Animais , Anticorpos Antivirais/metabolismo , Bovinos , Linhagem Celular , Doença Nodular Cutânea/imunologia , Vírus da Doença Nodular Cutânea/imunologia , Vírus da Doença Nodular Cutânea/patogenicidade , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Soroconversão , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacinas Virais/classificação , Vacinas Virais/genética , Vacinas Virais/imunologia
5.
Infect Immun ; 87(12)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31548316

RESUMO

Swine erysipelas is caused by the Gram-positive pathogen Erysipelothrix rhusiopathiae The swine erysipelas live vaccine in Japan, the E. rhusiopathiae Koganei 65-0.15 strain (Koganei), has been reported to cause arthritis and endocarditis. To develop a vaccine with increased safety, we used a virulent Fujisawa strain to construct transposon mutants for a total of 651 genes, which covered 38% of the coding sequence of the genome. We screened the mutants for attenuation by inoculating mice with 108 CFU of each mutant and subsequently assessed protective capability by challenging the surviving mice with 103 CFU (102 times the 50% lethal dose) of the Fujisawa strain. Of the 23 attenuated mutants obtained, 6 mutants were selected and evaluated for protective capability in pigs by comparison to that of the Koganei strain. A mutant in the ERH_0432 (tagF) gene encoding a putative CDP-glycerol glycerophosphotransferase was found to be highly attenuated and to induce humoral and cell-mediated immune responses in conventional pigs. An in-frame deletion mutant of the gene, the Δ432 mutant, was constructed, and attenuation was further confirmed in germfree piglets; three of four piglets subcutaneously inoculated with 109 CFU of the Δ432 mutant showed no apparent clinical symptoms, whereas all four of the Koganei-inoculated piglets died 3 days after inoculation. It was confirmed that conventional pigs inoculated orally or subcutaneously with the Δ432 strain were almost completely protected against lethal challenge infection. Thus, the tagF homolog mutant of E. rhusiopathiae represents a safe vaccine candidate that can be administered via the oral and subcutaneous routes.


Assuntos
Vacinas Bacterianas/imunologia , Infecções por Erysipelothrix/prevenção & controle , Erysipelothrix/genética , Erysipelothrix/imunologia , Doenças dos Suínos/prevenção & controle , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Animais , Elementos de DNA Transponíveis/genética , Erysipelothrix/patogenicidade , Infecções por Erysipelothrix/imunologia , Feminino , Camundongos , Suínos , Doenças dos Suínos/imunologia , Doenças dos Suínos/microbiologia , Vacinas Atenuadas/imunologia
6.
Nat Commun ; 10(1): 3950, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477704

RESUMO

Immunization with attenuated whole Plasmodium sporozoites constitutes a promising vaccination strategy. Compared to replication-deficient parasites, immunization with replication-competent parasites confers better protection and also induces a type I IFN (IFN-1) response, but whether this IFN-1 response has beneficial or adverse effects on vaccine-induced adaptive immunity is not known. Here, we show that IFN-1 signaling-deficient mice immunized with replication-competent sporozoites exhibit superior protection against infection. This correlates with superior CD8 T cell memory including reduced expression of the exhaustion markers PD-1 and LAG-3 on these cells and increased numbers of memory CD8 T cells in the liver. Moreover, the adoptive transfer of memory CD8 T cells from the livers of previously immunized IFN-1 signaling-deficient mice confers greater protection against liver stage parasites. However, the detrimental role of IFN-1 signaling is not CD8 T cell intrinsic. Together, our data demonstrate that liver stage-engendered IFN-1 signaling impairs hepatic CD8 T cell memory via a CD8 T cell-extrinsic mechanism.


Assuntos
Imunidade Adaptativa/imunologia , Eritrócitos/imunologia , Imunidade Inata/imunologia , Malária/imunologia , Plasmodium yoelii/imunologia , Esporozoítos/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/parasitologia , Eritrócitos/parasitologia , Feminino , Imunização , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/parasitologia , Malária/parasitologia , Malária/prevenção & controle , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium yoelii/fisiologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia
7.
Parasitol Res ; 118(10): 3033-3041, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407118

RESUMO

Coccidiosis, caused by the infection of Eimeria parasites, is one of the most common diseases in domestic rabbits. Live anticoccidial vaccine formulated with attenuated precocious lines of pathogenic eimerian parasites is expected to be valuable for the control of rabbit coccidiosis as a similar strategy to produce anticoccidial vaccines against chicken coccidiosis has being used for several decades. Eimeria media, moderate pathogenic, is widespread in China. Therefore, attenuated anticoccidial vaccines against rabbit coccidiosis should contain vaccine strain(s) of E. media. In this study, a precocious line of E. media (Empre) was selected by collecting and propagating the early excreted oocysts with 16 successive generations. The prepatent period of Empre reduced from 108 h of its parental strain (Emwt) to 70 h. The fecundity of Empre was about 1/10 to 1/3 lower than that of Emwt. Each sporocyst of Empre sporulated oocyst contained only one large refractile body instead of two smaller ones seen in the parental strain. When vaccinated with 1 × 103 or 1 × 104 precocious line oocysts, the rabbits were completely protected against homologous challenge with the parental strain 14 days post challenge by terms of body weight gain and oocyst output counting, indicating the efficacy of Empre. Meanwhile, all immunized rabbits showed no clinical sign post immunization, indicating the safety of Empre. For co-immunization, 1 × 103Empre oocysts and 5 × 102 oocysts of a precocious line of E. intestinalis (EIP8) were inoculated to each rabbit in a trial. No diarrhea or mortality was found after vaccination, and the weight gains of the vaccinated group were similar to that of unvaccinated-unchallenged control (UUC) group, while the weight gains of the vaccinated group were similar to that of unvaccinated-unchallenged control (UUC) group (P > 0.05), but significantly higher than that of UCC group (P < 0.01) after challenge, indicating it is safe and effective when using co-immunization. These results together show that Empre, as a precocious line, is a good candidate of precocious line of E. media for anticoccidial vaccine development.


Assuntos
Coccidiose/veterinária , Eimeria/patogenicidade , Infecções Protozoárias em Animais/parasitologia , Animais , Coccidiose/parasitologia , Coccidiose/prevenção & controle , Eimeria/crescimento & desenvolvimento , Eimeria/imunologia , Eimeria/fisiologia , Imunização/veterinária , Oocistos/crescimento & desenvolvimento , Oocistos/imunologia , Oocistos/patogenicidade , Infecções Protozoárias em Animais/prevenção & controle , Vacinas Protozoárias/imunologia , Coelhos , Reprodução , Vacinas Atenuadas/imunologia
8.
Int J Infect Dis ; 87: 32-38, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442625

RESUMO

BACKGROUND: Mycobacterium bovis BCG is a live, attenuated tuberculosis vaccine. While the vaccine protects infants from tuberculosis, complications including disseminated infections have been reported following vaccination. Genetically diverse BCG sub-strains now exist following continuous passaging of the original Pasteur strain for vaccine manufacture. This genetic diversity reportedly influences the severity of disseminated BCG infections and the efficacy of BCG immunization. METHODS: M. bovis BCG was isolated from infants suspected of being infected with tuberculosis. The whole genome of the clinical isolates and BCG Moscow were sequenced using Illumina Miseq and the sequences were analysed using CLC Genomics Workbench 7.0, PhyResSE v1.0, and Parsnp. RESULTS AND CONCLUSIONS: Genetic variations between the clinical strains and the reference BCG Copenhagen were identified. The clinical strains shared only one mutation in a secretion protein. Mutations were identified in various antibiotic resistance genes in the BCG isolates, which suggests their potential as multidrug-resistant (MDR) phenotypes. Phylogenetic analysis showed that the two isolates were distantly related, and the M1_S48 clinical isolate was closely related to M. bovis BCG Moscow. The phylogenomics results imply that two different BCG strains may be circulating in South Africa. However, it is difficult to associate the BCG vaccine strain administered and the BCG strain supplied with specific adverse events, as BCGiosis is under-reported. This study presents background genomic information for future surveillance and tracking of the distribution of BCGiosis-associated mycobacteria. It is also the first to report on the genomes of clinical BCG strains in Africa.


Assuntos
Vacina BCG/efeitos adversos , Mycobacterium bovis/classificação , Filogenia , Tuberculose/virologia , Vacina BCG/genética , Vacina BCG/imunologia , Sequência de Bases , Feminino , Humanos , Lactente , Masculino , Mutação , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Mycobacterium bovis/isolamento & purificação , África do Sul/epidemiologia , Tuberculose/epidemiologia , Tuberculose/etiologia , Tuberculose/prevenção & controle , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia
9.
Ticks Tick Borne Dis ; 10(6): 101270, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31445874

RESUMO

Protection against the intraerythrocytic protozoan parasite Babesia bovis depends on both strong innate and adaptive immune response, this latter involving the presentation of parasite antigens to CD4+ T-lymphocytes by professional antigen-presenting cells. Secretion of Th1 cytokines by CD4+ T cell is also very important for isotype switching to IgG2, the best opsonising antibody isotype in cattle, to target extracellular parasites and parasite antigens displayed at the erythrocyte surface. In the field of vaccinology, heterologous prime-boost schemes combining protein-adjuvant formulations with a modified vaccinia Ankara vector expressing the same antigen have demonstrated the induction of both humoral and cellular immune responses. It has been previously demonstrated that MVA-infected dendritic cells can present antigens in the context of MHC II and activate CD4+ T cell. These results support the use of the MVA viral vector for a pathogen like Babesia bovis, which only resides within erythrocytes. In this study, 13-15-months-old Holstein-Friesian steers were immunised with a subunit vaccine as a prime and a modified vaccinia Ankara vector as a boost, both expressing a chimeric multi-antigen (rMABbo - rMVA). This antigen includes the immunodominant B and T cell epitopes of three B. bovis proteins: merozoite surface antigen - 2c (MSA - 2c), rhoptry associated protein 1 (RAP - 1) and heat shock protein 20 (HSP20). Responses were compared with the Babesia bovis live attenuated vaccine used in Argentina (R1A). Eleven weeks after the first immunisation, all bovines were challenged by the inoculation of a virulent B. bovis strain. All groups were monitored daily for hyperthermia and reduction of packed cell volume. Both the rMABbo - rMVA and R1A vaccinated animals developed high titters of total IgG antibodies and an antigen-specific Th1 cellular response before and after challenge. However, all rMABbo - rMVA steers showed clinical signs of disease upon challenge. Only the R1A live vaccine group developed an immune response associated with in vitro neutralising antibodies at a level that significantly inhibited the parasite invasion. The lack of protection observed with this recombinant formulation indicates the need to perform further basic and clinical studies in the bovine model in order to achieve the desired effectiveness. This is the first report in which a novel vaccine candidate against Babesia bovis was constructed based on a recombinant and rationally designed viral vector and evaluated in the biological model of the disease.


Assuntos
Babesia bovis/imunologia , Babesiose/prevenção & controle , Doenças dos Bovinos/prevenção & controle , Vacinas Protozoárias/imunologia , Vacinação/veterinária , Animais , Anticorpos Neutralizantes/imunologia , Babesiose/imunologia , Bovinos , Doenças dos Bovinos/imunologia , Epitopos/imunologia , Imunidade Celular , Imunidade Humoral , Masculino , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Vacinas Atenuadas/imunologia , Vírus Vaccinia/imunologia
10.
PLoS Negl Trop Dis ; 13(8): e0007601, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31374086

RESUMO

Genotype III (GIII) Japanese encephalitis virus (JEV) predominance has gradually been replaced by genotype I (GI) over the last 20 years in many Asian countries. This genotype shift raises concerns about the protective efficacy of Japanese encephalitis (JE) vaccines, as all of the currently licensed JE vaccines are derived from GIII strains. In this study, we conducted vaccination-challenge protection assays to evaluate the cross-protective efficacy of GI- or GIII-derived vaccines against the challenge of a heterologous genotype using a mouse challenge model. Titration of the neutralizing antibodies elicited by SA14-14-2 live-attenuated JE vaccine (SA14-14-2 vaccine), a GIII-derived vaccine, indicated that the titer of neutralizing antibodies specific to heterologous genotype GI stain was significantly lower than that specific to homologous genotype GIII strain in both pigs and mice immunized with the SA14-14-2 vaccine. Vaccination of mice with SA14-14-2 vaccine or a GIII-inactivated vaccine at high and medium doses completely protected vaccinated mice against challenge with the homologous genotype GIII strains, but failed to provide the vaccinated mice complete protection against the challenge of heterologous genotype GI strains. The protection rates against GI strain challenge were 60%-80%, showing that these vaccines were partially protective against GI strain challenge. Additionally, vaccination of mice with a GI-inactivated vaccine conferred 100% protection against the challenge of homologous genotype GI strains, but 50%-90% protection against the challenge of heterologous genotype GIII strains, showing a reduced protective efficacy of a GI-derived vaccine against GIII strain challenge. Overall, these observations demonstrated a partial cross-protection between GI and GIII strains and suggested a potential need for new JE vaccine strategies, including options like a bivalent vaccine, to control both genotype infection.


Assuntos
Proteção Cruzada/imunologia , Vírus da Encefalite Japonesa (Espécie)/genética , Vírus da Encefalite Japonesa (Espécie)/imunologia , Encefalite Japonesa/prevenção & controle , Genótipo , Vacinas contra Encefalite Japonesa/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Ásia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de Proteína , Suínos , Vacinação , Vacinas Atenuadas/imunologia , Vacinas de Produtos Inativados
11.
Fish Shellfish Immunol ; 93: 924-933, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31374315

RESUMO

Our previous studies demonstrated that the deletion of D2 fragment in tilapia Streptococcus agalactiae(GBS) attenuated strain YM001 is the main reason for the loss of virulence to tilapia. In this study, a Δ2 mutant that deletion of D2 fragment in parental virulent strain HN016 was constructed, and the safety, stability, immunogenicity, and growth characteristics, as well as the virulence mechanism of Δ2 mutant were evaluated. The results showed that Δ2 mutant was not pathogenic to tilapia, and the virulent revertants were not observed after 50 generations of passage. The RPS reached 96.11% at 15 days and 93.05% at 30 days, respectively, after intraperitoneal injection, while RPS reached 74.80% at 15 days and 53.16% at 30 days, respectively, after oral immunization. The growth of Δ2 mutant was significantly faster than YM001, and genes that were enriched in the nitrogen metabolism and arginine biosynthesis signaling pathway (arc, glnA, and gdhA) were identified as important candidate genes responsible for growth rate of S. agalactiae. The absence of D2 fragment affected the expression of Sip, therefore influencing the bacterial virulence. Altogether, this study demonstrated that deletion of D2 fragment in HN016 causes the loss of virulence to tilapia, and Δ2 mutant is a promising, better attenuated oral vaccine strain of S. agalactiae compared to YM001.


Assuntos
Vacinas Bacterianas/imunologia , Sequência de Bases , Ciclídeos/imunologia , Doenças dos Peixes/prevenção & controle , Deleção de Sequência , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae/imunologia , Animais , Doenças dos Peixes/imunologia , Técnicas de Inativação de Genes/veterinária , Sorogrupo , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/prevenção & controle , Streptococcus agalactiae/patogenicidade , Vacinas Atenuadas/imunologia , Virulência
12.
Bull Exp Biol Med ; 167(3): 384-387, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31346883

RESUMO

We studied the constellation of genes encoding polymerase complex proteins of master donor viruses for Russian live attenuated influenza vaccine type B. Reassortants of the reserve attenuation donor B/Leningrad/14/17/55 with B/USSR/60/69 master donor virus currently used for manufacturing seasonal influenza vaccine were prepared and examined. Most reassortants obtained by the classical reassortment method inherited all genes from the B/Leningrad/14/17/55 virus except the gene encoding PB1 subunit of the polymerase complex. One reassortant was selected for further evaluation of the role of PB1 gene. Greater attenuation of the strain for experimental animals (mice) in comparison with the original strains was demonstrated. This indicates high degree of constellation of genes of cold-adapted master donor viruses and the important compensating role of amino acid substitutions in the PB1 protein of B/Leningrad/14/17/55 donor virus in preventing viral hyperattenuation.


Assuntos
Influenza Humana/prevenção & controle , Influenzavirus B/genética , Proteínas Virais/genética , Substituição de Aminoácidos/genética , Animais , Embrião de Galinha , Temperatura Baixa , Humanos , Vacinas contra Influenza/imunologia , Influenzavirus B/imunologia , Camundongos , Vírus Reordenados/genética , Vírus Reordenados/imunologia , Vacinas Atenuadas/imunologia
13.
Comp Immunol Microbiol Infect Dis ; 65: 128-131, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31300101

RESUMO

Sheep pox is a disease of veterinary concern to small ruminant producers and veterinary diagnosticians, because of the associated tangible economic losses. The epidemiological analysis of sheep pox, among vaccinated sheep flock in Algeria from 2007 to 2016, showed that the disease outbreaks occurred every year and across all Algeria region with an average of 44.9 outbreaks per year, these outbreaks correlate with the region climate, the flocks' density and the transhumance practices. The one-year post vaccination antibody kinetics evaluation study of the commercially used vaccine in Algeria demonstrated a mild humoral response, the neutralization index range between 0.73 and 1.22. Therefore, the present study recommends a challenge study, using a virulent local strain, to evaluate the vaccine efficacy. Furthermore, quality control approach for the vaccine production processes is required.


Assuntos
Anticorpos Antivirais/sangue , Surtos de Doenças , Infecções por Poxviridae/veterinária , Doenças dos Ovinos/epidemiologia , Potência de Vacina , Vacinas Virais/imunologia , Argélia/epidemiologia , Animais , Cinética , Testes de Neutralização , Infecções por Poxviridae/epidemiologia , Estudos Retrospectivos , Ovinos , Doenças dos Ovinos/virologia , Vacinação , Vacinas Atenuadas/imunologia , Vacinas Virais/normas
14.
Comp Immunol Microbiol Infect Dis ; 65: 181-188, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31300111

RESUMO

Goatpox (GTP), sheeppox (SPP) and lumpy skin disease (LSD) are three severe diseases of goat, sheep and cattle. Their typical clinical symptoms are characterized by vesicles, papules, nodules, pustules and scabs on animal skins. The GTP, SPP and LSD are caused by goatpox virus (GTPV), sheeppox virus (SPPV) and lumpy skin disease virus (LSDV), respectively, all of which belong to the genus Capripoxvirus in the family Poxviridae. Several capripoxvirus (CaPV) isolates have been virulently attenuated through serial passaging in vitro for production of live vaccines. CaPV-based vector systems have been broadly used to construct recombinant vaccines for delivering foreign antigens, many of which have been demonstrated to induce effective immune protections. Homologous recombination is the most commonly used method for constructing recombinant CaPVs. Here, we described a methodology for generation of recombinant CaPVs by the homologous recombination, and further reviewed CaPV-vectored vaccines for delivering foreign antigens.


Assuntos
Capripoxvirus/genética , DNA Viral/genética , Vetores Genéticos , Infecções por Poxviridae/veterinária , Animais , Ensaios Clínicos Veterinários como Assunto , Engenharia Genética , Doenças das Cabras/prevenção & controle , Doenças das Cabras/virologia , Cabras , Recombinação Homóloga , Infecções por Poxviridae/prevenção & controle , Ovinos , Doenças dos Ovinos/prevenção & controle , Doenças dos Ovinos/virologia , Vacinas Atenuadas/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virais/genética , Vacinas Virais/imunologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31300122

RESUMO

Brucella is an intracellular pathogen that causes abortion in domestic animals and undulant fever in humans. Due to the lack of a human vaccine against brucellosis, animal vaccines play an important role in the management of animal and human brucellosis for decades. Strain 19, RB51 and Rev1 are the approved Brucella spp. vaccine strains that are most commonly used to protect livestock against infection and abortion. However, due to some disadvantages of these vaccines, numerous studies have been conducted for the development of effective vaccines that could also be used in other susceptible animals. In this review, we compare different aspects of immunogenic antigens that have been a candidate for the brucellosis vaccine.


Assuntos
Antígenos de Bactérias/imunologia , Vacina contra Brucelose/imunologia , Brucella abortus/imunologia , Brucelose/veterinária , Animais , Brucella abortus/patogenicidade , Brucelose/imunologia , Brucelose/prevenção & controle , Feminino , Humanos , Imunogenicidade da Vacina , Gado/microbiologia , Gravidez , Vacinas Atenuadas/imunologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-31300124

RESUMO

S. Choleraesuis (Choleraesuis) and S. Typhimurium (Typhimurium) cause salmonellosis in pigs and humans. The effects of vaccine strains pSV-less Typhimurium OU5048 and Choleraesuis OU7266 and SPI-2-mutant Choleraesuis SC2284 on the immune responses of pigs against Typhimurium, Choleraesuis, and S. Enteritidis (Enteritidis) with or without the virulence plasmid (pSV) were determined. After oral vaccination of three vaccine groups and challenge with Choleraesuis CN36, the level of Salmonella-specific IgG in sera and the bactericidal effects and superoxide generation of peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes (PMNs) against the above strains were determined using ELISA and NBT assay, respectively. Among three vaccine strains tested, OU7266 stimulated the highest Salmonella-specific IgG levels. Complement inactivation increased IgG concentration, while E. coli absorption reduced IgG levels. The pSV-containing strains were less resistant to serum killing than the pSV-less strains, and Enteritidis exhibited the lowest resistance to serum killing. Serovars tested, vaccine strains, and timeline periods postvaccination and challenge were important factors affecting superoxide production. The two Choleraesuis vaccine strains stimulated greater levels of superoxide from PMNs and PBMCs than the Typhimurium strains. The PMNs and PBMCs in challenged and vaccinated pigs reduced more superoxide than those in challenged hosts. In vaccinated hosts, pSV-less Salmonella strains triggered lower levels of PMN/PBMC-generated superoxide upon challenge than strains with pSV against Enteritidis and Choleraesuis. Overall, Choleraesuis OU7266 may be better than the other vaccine strains in generating the greatest IgG levels, serum bactericidal activity and superoxide levels. The pSV likely influences the immune responses.


Assuntos
Imunoglobulina G/sangue , Salmonelose Animal/prevenção & controle , Vacinas contra Salmonella/uso terapêutico , Doenças dos Suínos/prevenção & controle , Animais , Anticorpos Antibacterianos/sangue , Proteínas do Sistema Complemento/imunologia , Escherichia coli/imunologia , Escherichia coli/metabolismo , Feminino , Leucócitos Mononucleares/imunologia , Neutrófilos/imunologia , Espécies Reativas de Oxigênio/imunologia , Salmonella , Salmonelose Animal/imunologia , Vacinas contra Salmonella/imunologia , Salmonella typhimurium , Ensaios de Anticorpos Bactericidas Séricos , Suínos , Vacinação/veterinária , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/uso terapêutico
17.
BMC Vet Res ; 15(1): 247, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307464

RESUMO

BACKGROUND: Recent studies have hypothesized that circulation of classical swine fever virus (CSFV) variants when the immunity induced by the vaccine is not sterilizing might favour viral persistence. Likewise, in addition to congenital viral persistence, CSFV has also been proven to generate postnatal viral persistence. Under experimental conditions, postnatal persistently infected pigs were unable to elicit a specific immune response to a CSFV live attenuated vaccine via the mechanism known as superinfection exclusion (SIE). Here, we study whether subclinical forms of classical swine fever (CSF) may be present in a conventional farm in an endemic country and evaluate vaccine efficacy under these types of infections in field conditions. RESULTS: Six litters born from CSF-vaccinated gilts were randomly chosen from a commercial Cuban farm at 33 days of age (weaning). At this time, the piglets were vaccinated with a lapinized live attenuated CSFV C-strain vaccine. Virological and immunological analyses were performed before and after vaccination. The piglets were clinically healthy at weaning; however, 82% were viraemic, and the rectal swabs in most of the remaining 18% were positive. Only five piglets from one litter showed a specific antibody response. The tonsils and rectal swabs of five sows were CSFV positive, and only one of the sows showed an antibody response. After vaccination, 98% of the piglets were unable to clear the virus and to seroconvert, and some of the piglets showed polyarthritis and wasting after 36 days post vaccination. The CSFV E2 glycoprotein sequences recovered from one pig per litter were the same. The amino acid positions 72(R), 20(L) and 195(N) of E2 were identified in silico as positions associated with adaptive advantage. CONCLUSIONS: Circulation of chronic and persistent CSF infections was demonstrated in field conditions under a vaccination programme. Persistent infection was predominant. Here, we provide evidence that, in field conditions, subclinical infections are not detected by clinical diagnosis and, despite being infected with CSFV, the animals are vaccinated, rather than diagnosed and eliminated. These animals are refractory to vaccination, likely due to the SIE phenomenon. Improvement of vaccination strategies and diagnosis of subclinical forms of CSF is imperative for CSF eradication.


Assuntos
Vírus da Febre Suína Clássica/imunologia , Peste Suína Clássica/imunologia , Peste Suína Clássica/patologia , Vacinas Atenuadas/imunologia , Vacinas Virais/imunologia , Sequência de Aminoácidos , Animais , Peste Suína Clássica/virologia , Vírus da Febre Suína Clássica/isolamento & purificação , Cuba , Feminino , Superinfecção/veterinária , Superinfecção/virologia , Suínos , Vacinação/veterinária
18.
Nat Med ; 25(8): 1218-1224, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308506

RESUMO

Flaviviral infections result in a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe disease. Although the correlates of severe disease have been explored1-4, the pathophysiology that differentiates symptomatic from asymptomatic infection remains undefined. To understand the molecular underpinnings of symptomatic infection, the blood transcriptomic and metabolomic profiles of individuals were examined before and after inoculation with the live yellow fever viral vaccine (YF17D). It was found that individuals with adaptive endoplasmic reticulum (ER) stress and reduced tricarboxylic acid cycle activity at baseline showed increased susceptibility to symptomatic outcome. YF17D infection in these individuals induced maladaptive ER stress, triggering downstream proinflammatory responses that correlated with symptomatic outcome. The findings of the present study thus suggest that the ER stress response and immunometabolism underpin symptomatic yellow fever and possibly even other flaviviral infections. Modulating either ER stress or metabolism could be exploited for prophylaxis against symptomatic flaviviral infection outcome.


Assuntos
Estresse do Retículo Endoplasmático , Vacina contra Febre Amarela/imunologia , Febre Amarela/metabolismo , Adulto , Ciclo do Ácido Cítrico , Suscetibilidade a Doenças , Humanos , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Vacinas Atenuadas/imunologia , Febre Amarela/etiologia
19.
Nat Commun ; 10(1): 2981, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278315

RESUMO

Streptococcus pneumoniae is the main bacterial pathogen involved in pneumonia. Pneumococcal acquisition and colonization density is probably affected by viral co-infections, the local microbiome composition and mucosal immunity. Here, we report the interactions between live-attenuated influenza vaccine (LAIV), successive pneumococcal challenge, and the healthy adult nasal microbiota and mucosal immunity using an experimental human challenge model. Nasal microbiota profiles at baseline are associated with consecutive pneumococcal carriage outcome (non-carrier, low-dense and high-dense pneumococcal carriage), independent of LAIV co-administration. Corynebacterium/Dolosigranulum-dominated profiles are associated with low-density colonization. Lowest rates of natural viral co-infection at baseline and post-LAIV influenza replication are detected in the low-density carriers. Also, we detected the fewest microbiota perturbations and mucosal cytokine responses in the low-density carriers compared to non-carriers or high-density carriers. These results indicate that the complete respiratory ecosystem affects pneumococcal behaviour following challenge, with low-density carriage representing the most stable ecological state.


Assuntos
Portador Sadio/imunologia , Vacinas contra Influenza/imunologia , Microbiota/imunologia , Mucosa Nasal/microbiologia , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Coinfecção/imunologia , Coinfecção/microbiologia , Coinfecção/prevenção & controle , Feminino , Voluntários Saudáveis , Humanos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/prevenção & controle , Streptococcus pneumoniae/patogenicidade , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Adulto Jovem
20.
Scand J Immunol ; 90(4): e12801, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31269273

RESUMO

Influenza virus is a major respiratory pathogen, and vaccination is the main method of prophylaxis. In 2012, the trivalent live attenuated influenza vaccine (LAIV) was licensed in Europe for use in children. Vaccine-induced antibodies directed against the main viral surface glycoproteins, haemagglutinin (HA) and neuraminidase (NA) play important roles in limiting virus infection. The objective of this study was to dissect the influenza-specific antibody responses in children and adults, and T cell responses in children induced after LAIV immunization to the A/H1N1 virus. Blood samples were collected pre- and at 28 and 56 days post-vaccination from 20 children and 20 adults. No increase in micro-neutralization (MN) antibodies against A/H1N1 was observed after vaccination. A/H1N1 stalk-specific neutralizing and NA-inhibiting (NI) antibodies were boosted in children after LAIV. Interferon γ-producing T cells increased significantly in children, and antibody-dependent cellular-mediated cytotoxic (ADCC) cell activity increased slightly in children after vaccination, although this change was not significant. The results indicate that the NI assay is more sensitive to qualitative changes in serum antibodies after LAIV. There was a considerable difference in the immune response in children and adults after vaccination, which may be related to priming and previous influenza history. Our findings warrant further studies for evaluating LAIV vaccination immunogenicity.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Vacinas Atenuadas/imunologia , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Criança , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Imunidade Humoral , Masculino , Vacinação
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