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1.
Nature ; 577(7788): 95-102, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31894150

RESUMO

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide1. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission1,2. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography-computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis.


Assuntos
Administração Intravenosa , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Tuberculose/prevenção & controle , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Macaca mulatta , Tuberculose/imunologia , Vacinação/normas
2.
Infect Immun ; 86(2)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29203540

RESUMO

Clinical trials of novel tuberculosis (TB) vaccines are expensive, while global resources for TB vaccine development are limited. Therefore, there is a need for robust and predictive preclinical data to support advancement of candidate vaccines into clinical trials. Here, we provide a rationale for using the nonhuman primate as an essential component of these efforts, as well as guidance to the TB community for standardizing experimental design and aligning endpoints to facilitate development of new TB vaccines.


Assuntos
Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Vacinas contra a Tuberculose/imunologia , Vacinas contra a Tuberculose/isolamento & purificação , Tuberculose/prevenção & controle , Animais , Primatas
3.
Vaccine Insights ; 1(3): 165-181, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37091190

RESUMO

Immunization strategies against tuberculosis (TB) that confer better protection than neonatal vaccination with the 101-year-old Bacille Calmette-Guerin (BCG) are urgently needed to control the epidemic, but clinical development is hampered by a lack of established immune correlates of protection (CoPs). Two phase 2b clinical trials offer the first opportunity to discover human CoPs against TB. Adolescent BCG re-vaccination showed partial protection against Mycobacterium tuberculosis (Mtb) infection, as measured by sustained IFNγ release assay (IGRA) conversion. Adult M72/AS01E vaccination showed partial protection against pulmonary TB. We describe two collaborative research programs to discover CoPs against TB and ensure rigorous, streamlined use of available samples, involving international immunology experts in TB and state-of-the-art technologies, sponsors and funders. Hypotheses covering immune responses thought to be important in protection against TB have been defined and prioritized. A statistical framework to integrate the data analysis strategy was developed. Exploratory analyses will be performed to generate novel hypotheses.

4.
Blood ; 113(23): 5868-77, 2009 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-19304955

RESUMO

Improving the potency of immune responses is paramount among issues concerning vaccines against deadly pathogens. IL-28B belongs to the newly described interferon lambda (IFNlambda) family of cytokines, and has not yet been assessed for its potential ability to influence adaptive immune responses or act as a vaccine adjuvant. We compared the ability of plasmid-encoded IL-28B to boost immune responses to a multiclade consensus HIV Gag plasmid during DNA vaccination with that of IL-12. We show here that IL-28B, like IL-12, is capable of robustly enhancing adaptive immunity. Moreover, we describe for the first time how IL-28B reduces regulatory T-cell populations during DNA vaccination, whereas IL-12 increases this cellular subset. We also show that IL-28B, unlike IL-12, is able to increase the percentage of splenic CD8(+) T cells in vaccinated animals, and that these cells are more granular and have higher antigen-specific cytolytic degranulation compared with cells taken from animals that received IL-12 as an adjuvant. Lastly, we report that IL-28B can induce 100% protection from mortality after a lethal influenza challenge. These data suggest that IL-28B is a strong candidate for further studies of vaccine or immunotherapy protocols.


Assuntos
Adaptação Biológica/imunologia , Citocinas/metabolismo , Imunidade Celular/imunologia , Interleucina-12/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adjuvantes Imunológicos , Animais , Especificidade de Anticorpos/imunologia , Células Cultivadas , Citocinas/genética , Feminino , Produtos do Gene gag/farmacologia , Imunoglobulina G/imunologia , Interferon gama/metabolismo , Interleucina-12/genética , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Plasmídeos/genética , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/citologia , Fator de Crescimento Transformador beta/metabolismo , Vacinação
5.
Tuberculosis (Edinb) ; 126: 102040, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310626

RESUMO

Two proof of concept clinical trials with TB vaccines demonstrate that new approaches can prevent sustained TB infection in adolescents (BCG revaccination) and TB disease in adults (M72/ASO1E) (Nemes et al., 2018; Tait et al., 2019) [1,2]. Both approaches are in late stage development and provide motivation and rationale to invest into a global TB vaccine pipeline. This pipeline needs to be diverse to address TB-specific challenges including variation in target populations, uncertainties in animal model predictivity and lack of immune correlates of protection. It requires that individual vaccine candidates must be advanced rationally and that the global pipeline must be managed in the most nimble and resource-efficient way, especially in the current constrained funding environment. The TB Vaccine Development Pathway is a webtool which has been developed as an offer to the field to provide a source of information and guidance covering vaccine development from discovery to implementation. It is underpinned by generic and TB vaccine-specific guidelines, regulatory frameworks and best practice, and was compiled by a multi-disciplinary team of scientific and technical experts with the input of the TB vaccine community. The Pathway is a unique tool to guide and accelerate the development of TB vaccine candidates and may be useful for other vaccine development fields.


Assuntos
Desenvolvimento de Medicamentos/tendências , Imunização Secundária/métodos , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/farmacologia , Tuberculose/prevenção & controle , Humanos , Estudos Retrospectivos
6.
NPJ Vaccines ; 6(1): 4, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397991

RESUMO

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-γ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns.

7.
J Virol ; 83(9): 4624-30, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19211745

RESUMO

Avian influenza highlights the need for novel vaccination techniques that would allow for the rapid design and production of safe and effective vaccines. An ideal platform would be capable of inducing both protective antibodies and potent cellular immune responses. These potential advantages of DNA vaccines remain unrealized due to a lack of efficacy in large animal studies and in human trials. Questions remain regarding the potential utility of cellular immune responses against influenza virus in primates. In this study, by construct optimization and in vivo electroporation of synthetic DNA-encoded antigens, we observed the induction of cross-reactive cellular and humoral immune responses individually capable of providing protection from influenza virus infection in the rhesus macaque. These studies advance the DNA vaccine field and provide a novel, more tolerable vaccine with broad immunogenicity to avian influenza virus. This approach appears important for further investigation, including studies with humans.


Assuntos
Virus da Influenza A Subtipo H5N1/imunologia , Virus da Influenza A Subtipo H5N1/patogenicidade , Vacinas contra Influenza/imunologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Infecções por Orthomyxoviridae/prevenção & controle , Vacinas de DNA/imunologia , Animais , Eletroporação , Vetores Genéticos/genética , Vacinas contra Influenza/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/transmissão , Plasmídeos/genética , Vacinas de DNA/genética , Replicação Viral
8.
NPJ Vaccines ; 5(1): 39, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32435513

RESUMO

Tuberculosis (TB) still is the principal cause of death from infectious disease and improved vaccination strategies are required to reduce the disease burden and break TB transmission. Here, we investigated different routes of administration of vectored subunit vaccines based on chimpanzee-derived adenovirus serotype-3 (ChAd3) for homologous prime-boosting and modified vaccinia virus Ankara (MVA) for heterologous boosting with both vaccine vectors expressing the same antigens from Mycobacterium tuberculosis (Ag85B, ESAT6, Rv2626, Rv1733, RpfD). Prime-boost strategies were evaluated for immunogenicity and protective efficacy in highly susceptible rhesus macaques. A fully parenteral administration regimen was compared to exclusive respiratory mucosal administration, while parenteral ChAd3-5Ag prime-boosting and mucosal MVA-5Ag boosting were applied as a push-and-pull strategy from the periphery to the lung. Immune analyses corroborated compartmentalized responses induced by parenteral versus mucosal vaccination. Despite eliciting TB-specific immune responses, none of the investigational regimes conferred a protective effect by standard readouts of TB compared to non-vaccinated controls, while lack of protection by BCG underpinned the stringency of this non-human primate test modality. Yet, TB manifestation after full parenteral vaccination was significantly less compared to exclusive mucosal vaccination.

9.
Immunology ; 128(1 Suppl): e612-20, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19740322

RESUMO

DNA vaccination is a novel immunization strategy that has great potential for the development of vaccines and immune therapeutics. This strategy has been highly effective in mice, but is less immunogenic in non-human primates and in humans. Enhancing DNA vaccine potency remains a challenge. It is likely that antigen-presenting cells (APCs), and especially dendritic cells (DCs), play a significant role in the presentation of the vaccine antigen to the immune system. A new study reports the synergistic recruitment, expansion and activation of DCs in vivo by high-mobility group box 1 (HMGB1) protein. Such combinational strategies for delivering vaccine in a single, simple platform will hypothetically bolster the cellular immunity in vivo. Here, we combined plasmid encoding human immunodeficiency virus-1 (HIV-1) Gag and Env with an HMGB1 plasmid as a DNA adjuvant in BALB/c mice (by intramuscular immunization via electroporation), and humoral and cellular responses were measured. Co-administration of this potent immunostimulatory adjuvant strongly enhanced the cellular interferon-gamma (IFN-gamma) and humoral immune response compared with that obtained in mice immunized with vaccine only. Our results show that co-immunization with HMGB1 can have a strong adjuvant activity, driving strong cellular and humoral immunity that may be an effective immunological adjuvant in DNA vaccination against HIV-1.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , HIV-1/imunologia , Proteína HMGB1/imunologia , Vacinas de DNA/imunologia , Vacinas contra a AIDS/genética , Adjuvantes Imunológicos/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos/sangue , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Vetores Genéticos/imunologia , Vetores Genéticos/metabolismo , Proteína HMGB1/genética , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Vacinas de DNA/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
10.
J Virol ; 82(23): 11536-44, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18799583

RESUMO

Chronic viral infection is characterized by the functional impairment of virus-specific T-cell responses. Recent evidence has suggested that the inhibitory receptor programmed death 1 (PD-1) is specifically upregulated on antigen-specific T cells during various chronic viral infections. Indeed, it has been reported that human immunodeficiency virus (HIV)-specific T cells express elevated levels of PD-1 and that this expression correlates with the viral load and inversely with CD4(+) T-cell counts. More importantly, antibody blockade of the PD-1/PD-L1 pathway was sufficient to both increase and stimulate virus-specific T-cell proliferation and cytokine production. However, the mechanisms that mediate HIV-induced PD-1 upregulation are not known. Here, we provide evidence that the HIV type 1 (HIV-1) accessory protein Nef can transcriptionally induce the expression of PD-1 during infection in vitro. Nef-induced PD-1 upregulation requires its proline-rich motif and the activation of the downstream kinase p38. Further, inhibition of Nef activity by p38 MAPK inhibitor effectively blocked PD-1 upregulation, suggesting that p38 MAPK activation is an important initiating event in Nef-mediated PD-1 expression in HIV-1-infected cells. These data demonstrate an important signaling event of Nef in HIV-1 pathogenesis.


Assuntos
Antígenos CD/genética , Proteínas Reguladoras de Apoptose/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Síndrome da Imunodeficiência Adquirida/metabolismo , Antígenos CD/biossíntese , Proteínas Reguladoras de Apoptose/biossíntese , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Receptor de Morte Celular Programada 1 , Regulação para Cima
11.
Tuberculosis (Edinb) ; 114: 47-53, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711157

RESUMO

A global BCG vaccine shortage began in 2013 which impacted availability for infant vaccinations, as well as preclinical studies and clinical trials of new TB vaccines. Stakeholders met in 2015 at McGill University in Montreal to discuss the shortage and potential mitigation strategies. Manufacturing BCG through a more tractable liquid fermentation process instead of the traditional pellicle growth method was considered a potentially viable strategy. This pilot program compared pellicle-grown and shake flask-grown BCG strains (as a first step towards modeling fermenter-produced BCG vaccine) in selected quality control assays, as well as mouse and guinea pig protection studies. Conventional pellicle-grown, lyophilized BCG WHO Reference Reagents (Danish, Moreau, Russian, Tokyo strains) were obtained from the National Institute for Biological Standards and Control (NIBSC), UK. Strains were grown in shake flasks and glycerol stocks prepared. Shake flask-grown BCG culture preparations generally met the requirements of quality control testing at NIBSC. In mouse and guinea pig protection studies there were no significant differences in lung colony forming units (CFUs) between shake flask-grown and pellicle-grown preparations, with the exception of BCG Russian, where the shake flask-grown preparation protected better in mice (P = 0.0042), but the pellicle-grown preparation protected better in guinea pigs (P = 0.0015). Producing BCG vaccines by a more tractable liquid growth process could be a viable solution to the global BCG shortage.


Assuntos
Vacina BCG/normas , Técnicas Bacteriológicas/métodos , Mycobacterium bovis/crescimento & desenvolvimento , Animais , Vacina BCG/efeitos adversos , Vacina BCG/imunologia , Contagem de Colônia Microbiana , Feminino , Cobaias , Hipersensibilidade Tardia/etiologia , Camundongos Endogâmicos BALB C , Mycobacterium bovis/imunologia , Controle de Qualidade , Tuberculose/prevenção & controle
12.
NPJ Vaccines ; 4: 21, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31149352

RESUMO

Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10-30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01E or H56:CAF01 elicited ~0.1-0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5-1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis.

13.
Nat Med ; 24(2): 130-143, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29334373

RESUMO

Despite widespread use of the bacille Calmette-Guérin (BCG) vaccine, tuberculosis (TB) remains a leading cause of global mortality from a single infectious agent (Mycobacterium tuberculosis or Mtb). Here, over two independent Mtb challenge studies, we demonstrate that subcutaneous vaccination of rhesus macaques (RMs) with rhesus cytomegalovirus vectors encoding Mtb antigen inserts (hereafter referred to as RhCMV/TB)-which elicit and maintain highly effector-differentiated, circulating and tissue-resident Mtb-specific CD4+ and CD8+ memory T cell responses-can reduce the overall (pulmonary and extrapulmonary) extent of Mtb infection and disease by 68%, as compared to that in unvaccinated controls, after intrabronchial challenge with the Erdman strain of Mtb at ∼1 year after the first vaccination. Fourteen of 34 RhCMV/TB-vaccinated RMs (41%) across both studies showed no TB disease by computed tomography scans or at necropsy after challenge (as compared to 0 of 17 unvaccinated controls), and ten of these RMs were Mtb-culture-negative for all tissues, an exceptional long-term vaccine effect in the RM challenge model with the Erdman strain of Mtb. These results suggest that complete vaccine-mediated immune control of highly pathogenic Mtb is possible if immune effector responses can intercept Mtb infection at its earliest stages.


Assuntos
Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Vacina BCG/imunologia , Citomegalovirus/imunologia , Macaca mulatta/imunologia
14.
Int Rev Immunol ; 25(3-4): 99-123, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16818367

RESUMO

The field of DNA vaccine development began over 16 years ago with the observation that plasmid DNA could be injected into and expressed in vivo and drive adaptive immune responses. Since then, there has been great interest in developing this technology to create a new generation of vaccines with the ability to elicit both humoral and cellular immune responses from an inherently innocuous injection. However, DNA vaccines have yet to proceed past phase I/II clinical trials in humans--primarily due to a desire to induce more potent immune responses. This review will examine how DNA vaccines function to induce an immune response and how this information might be useful in future vaccine design.


Assuntos
Doenças Transmissíveis/imunologia , Plasmídeos/uso terapêutico , Vacinas de DNA/uso terapêutico , Animais , Controle de Doenças Transmissíveis/métodos , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Citocinas/imunologia , HIV/imunologia , Humanos , Imunidade Celular/imunologia , Influenza Humana/virologia , Plasmídeos/genética , Plasmídeos/imunologia , Saponinas/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologia
15.
PLoS One ; 11(12): e0168521, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27997597

RESUMO

BACKGROUND: The development of a novel tuberculosis vaccine is a leading global health priority. SRL172, an inactivated, whole-cell mycobacterial vaccine, was safe, immunogenic and reduced the incidence of culture-confirmed tuberculosis in a phase III trial in HIV-infected and BCG immunized adults in Tanzania. Here we describe the immunogenicity and protective efficacy of DAR-901, a booster vaccine against tuberculosis manufactured from the same seed strain using a new scalable method. METHODS: We evaluated IFN-γ responses by ELISpot and antibody responses by enzyme linked immunosorbent assay in C57BL/6 and BALB/c mice after three doses of DAR-901. In an aerosol challenge model, we evaluated the protective efficacy of the DAR-901 booster in C57BL/6 mice primed with BCG and boosted with two doses of DAR-901 at 4 dosage levels in comparison with homologous BCG boost. RESULTS: DAR-901 vaccination elicited IFN-γ responses to mycobacterial antigen preparations derived from both DAR-901 and Mycobacterium tuberculosis. DAR-901 immunization enhanced antibody responses to DAR-901 but not Mycobacterium tuberculosis lysate or purified protein derivative. Among animals primed with BCG, boosting with DAR-901 at 1 mg provided greater protection against aerosol challenge than a homologous BCG boost (lungs P = 0.036, spleen P = 0.028). CONCLUSIONS: DAR-901 induces cellular and humoral immunity and boosts protection from M. tuberculosis compared to a homologous BCG boost.


Assuntos
Vacina BCG/imunologia , Imunização Secundária , Imunogenicidade da Vacina , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Animais , Antígenos de Bactérias , Vacina BCG/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C
16.
Tuberculosis (Edinb) ; 96: 1-12, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26786648

RESUMO

Well characterised animal models that can accurately predict efficacy are critical to the development of an improved TB vaccine. The use of high dose challenge for measurement of efficacy in Non-human primate models brings the risk that vaccines with the potential to be efficacious against natural challenge could appear ineffective and thus disregarded. Therefore, there is a need to develop a challenge regimen that is more relevant to natural human infection. This study has established that ultra-low dose infection of macaques via the aerosol route can be reproducibly achieved and provides the first description of the development of TB disease in both rhesus and cynomolgus macaques following exposure to estimated retained doses in the lung of less than 10 CFU of Mycobacterium tuberculosis. CT scanning in vivo and histopathology revealed differences in the progression and burden of disease between the two species. Rhesus macaques exhibited a more progressive disease and cynomolgus macaques showed a reduced disease burden. The ability to deliver reproducible ultra-low dose aerosols to macaques will enable the development of refined models of M. tuberculosis infection for evaluation of the efficacy of novel tuberculosis vaccines that offers increased clinical relevance and improved animal welfare.


Assuntos
Exposição por Inalação , Pulmão/microbiologia , Macaca fascicularis , Macaca mulatta , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose Pulmonar/microbiologia , Aerossóis , Animais , Carga Bacteriana , Biópsia , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Progressão da Doença , Interações Hospedeiro-Patógeno , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/patologia , Masculino , Mycobacterium tuberculosis/imunologia , Especificidade da Espécie , Fatores de Tempo , Tomografia Computadorizada por Raios X , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia
17.
mBio ; 7(5)2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27651361

RESUMO

UNLABELLED: The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the "Collaborative Cross" project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines. IMPORTANCE: Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition in BCG efficacy. We found that the ability of BCG to protect mice with different genotypes was remarkably variable. The efficacy of BCG did not depend on the intrinsic susceptibility of the animal but, instead, correlated with qualitative differences in the immune responses to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provide a model system to develop interventions that will be useful in genetically diverse populations.


Assuntos
Vacina BCG/imunologia , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Tuberculose/genética , Tuberculose/prevenção & controle , Animais , Animais não Endogâmicos , Vacina BCG/administração & dosagem , Modelos Animais de Doenças , Variação Genética , Genótipo , Interações Hospedeiro-Patógeno/genética , Humanos , Camundongos , Mycobacterium tuberculosis/genética , Tuberculose/microbiologia
18.
DNA Cell Biol ; 23(4): 239-47, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15142381

RESUMO

New and effective approaches for inflammatory diseases based on novel mechanisms of action are needed. One potential source of anti-inflammatory drugs exists among viruses. Viruses have evolved to infect, replicate within, and kill human cells through diverse mechanisms. They accomplish this fact by finding ways to out with the host's complex immune machinery. It is possible that the viral proteins and pathways involved in the downregulation of host immune function during infection can be exploited as a therapeutic in diseases that result in the overactivity of the immune system. Indeed, the human immunodeficiency virus type 1 (HIV-1) protein, Vpr, affects cells in a number of ways that may prove useful for exploitation for the treatment of inflammatory diseases. Vpr has effects on T-cell proliferation, cytokine production, chemokine production, and Nuclear Factor kappa B (NF-kappaB)-mediated transcription. Importantly, it has been observed that Vpr downregulates NF-kappaB and the production of pro-inflammatory cytokines such as TNF-alpha, and IL-12. These activities are worthy of further examination for control of hyperinflammatory and hyperproliferative conditions.


Assuntos
Regulação para Baixo , Produtos do Gene vpr/uso terapêutico , HIV-1/fisiologia , Inflamação/terapia , NF-kappa B/metabolismo , Quimiocinas/metabolismo , Produtos do Gene vpr/metabolismo , Produtos do Gene vpr/fisiologia , Humanos , Interleucina-12/metabolismo , Modelos Biológicos , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Produtos do Gene vpr do Vírus da Imunodeficiência Humana
19.
Hum Vaccin Immunother ; 10(8): 2188-98, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25424922

RESUMO

Development of a broad-spectrum synthetic vaccine against TB would represent an important advance to the limited vaccine armamentarium against TB. It is believed that the esx family of TB antigens may represent important vaccine candidates. However, only 4 esx antigens have been studied as potential vaccine antigens. The challenge remains to develop a vaccine that simultaneously targets all 23 members of the esx family to induce enhanced broad-spectrum cell-mediated immunity. We sought to investigate if broader cellular immune responses could be induced using a multivalent DNA vaccine representing the esx family protein members delivered via electroporation. In this study, 15 designed esx antigens were created to cross target all members of the esx family. They were distributed into groups of 3 self-processing antigens each, resulting in 5 trivalent highly optimized DNA plasmids. Vaccination with all 5 constructs elicited robust antigen-specific IFN-γ responses to all encoded esx antigens and induced multifunctional CD4 Th1 and CD8 T cell responses. Importantly, we show that when all constructs are combined into a cocktail, the RSQ-15 vaccine, elicited substantial broad Ag-specific T cell responses to all esx antigens as compared with vaccination with BCG. Moreover, these vaccine-induced responses were highly cross-reactive with BCG encoded esx family members and were highly immune effective in a BCG DNA prime-boost format. Furthermore, we demonstrate the vaccine potential and immunopotent profile of several novel esx antigens never previously studied. These data highlight the likely importance of these novel immunogens for study as preventative or therapeutic synthetic TB vaccines in combination or as stand alone antigens.


Assuntos
Antígenos de Bactérias/imunologia , Imunidade Celular , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Animais , Antígenos de Bactérias/genética , Eletroporação , Interferon gama/metabolismo , Leucócitos Mononucleares/imunologia , Camundongos , Subpopulações de Linfócitos T/imunologia , Tuberculose/imunologia , Vacinas contra a Tuberculose/genética , Vacinação/métodos , Vacinas de DNA/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
20.
Nucl Med Biol ; 41(10): 777-84, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25195017

RESUMO

Nearly 20 years after the World Health Organization declared tuberculosis (TB) a global public health emergency, TB still remains a major global threat with 8.6 million new cases and 1.3 million deaths annually. Mycobacterium tuberculosis adapts to a quiescent physiological state, and is notable for complex interaction with the host, producing poorly-understood disease states ranging from latent infection to fully active disease. Of the approximately 2.5 billion people latently infected with M. tuberculosis, many will develop reactivation disease (relapse), years after the initial infection. While progress has been made on some fronts, the alarming spread of multidrug-resistant, extensively drug-resistant, and more recently totally-drug resistant strains is of grave concern. New tools are urgently needed for rapidly diagnosing TB, monitoring TB treatments and to allow unique insights into disease pathogenesis. Nuclear bioimaging is a powerful, noninvasive tool that can rapidly provide three-dimensional views of disease processes deep within the body and conduct noninvasive longitudinal assessments of the same patient. In this review, we discuss the application of nuclear bioimaging to TB, including the current state of the field, considerations for radioprobe development, study of TB drug pharmacokinetics in infected tissues, and areas of research and clinical needs that could be addressed by nuclear bioimaging. These technologies are an emerging field of research, overcome several fundamental limitations of current tools, and will have a broad impact on both basic research and patient care. Beyond diagnosis and monitoring disease, these technologies will also allow unique insights into understanding disease pathogenesis; and expedite bench-to-bedside translation of new therapeutics. Finally, since molecular imaging is readily available for humans, validated tracers will become valuable tools for clinical applications.


Assuntos
Diagnóstico por Imagem/métodos , Mycobacterium tuberculosis/isolamento & purificação , Medicina Nuclear , Tuberculose/diagnóstico , Humanos , Tuberculose/microbiologia
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