TB Vaccine Development Research Articles

Intravenous Immunization with Triple Auxotrophs of Mycobacterium tuberculosis : A novel vaccine strategy against tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis ( Mtb ), remains a leading infectious cause of mortality worldwide despite widespread use of the BCG vaccine and the availability of sterilizing pharmacopoeia. Recent research indicates that the intravenous administration of BCG confers sterilizing immunity against Mtb pulmonary challenge in non-human primates. However, while BCG is relatively safe, complications such as disseminated BCGosis have been observed in immunocompromised individuals. Double auxotrophic mutants of Mtb lacking the ability to synthesize leucine and pantothenate are safe and sterilized in immunocompromised mice and SIV-infected Rhesus macaques. We examined how immunization with a Mtb triple auxotrophic strain, mc 2 7902, which cannot synthesize leucine, pantothenate, and arginine, protects immunocompetent mice from a virulent Mtb infection. The route of immunization was a crucial factor for protection with mc 2 7902 with intravenous immunization being 100 times more effective in protecting immunocompetent mice from Mtb challenge when compared to conventional subcutaneous vaccination with BCG. To further increase the safety of the attenuated auxotroph for vaccine purposes, the type VII secretion system Esx1 responsible for BCG attenuation was deleted in mc 2 7902. When tested by prime-boost immunization of immunocompetent mice followed by aerosol challenge with virulent Mtb , mc 2 7902 Δ esx1 provided similar protection to mc 2 7902. This robust protection against Mtb infection conferred by mc 2 7902 and mc 2 7902 Δ esx1 in a mouse model paves the way for new TB vaccine development using highly attenuated, auxotrophic Mtb strains.

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study.

Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies. We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a "no-new-vaccine" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs. TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.

A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV.

SummaryBackgroundThe immunologic correlates of risk of Mycobacterium tuberculosis (Mtb) infection after BCG vaccination are unknown. The mechanism by which BCG influences the tuberculin skin test (TST) remains poorly understood. We evaluated CD4+ T-cell responses in infants exposed to HIV and uninfected (HEU) who received BCG at birth and examined their role in susceptibility to Mtb infection and influence on TST induration.MethodsHEU infants were enrolled in a randomised clinical trial of isoniazid (INH) to prevent Mtb infection in Kenya. We measured mycobacterial antigen-specific Th1 and Th17 cytokine responses at 6–10 weeks of age prior to INH randomisation and compared responses between Mtb infected and uninfected infants. Outcomes at 14 months of age included TST, QuantiFERON-Plus (QFT-Plus), and ESAT-6/CFP-10-specific non-IFN-γ cytokines measured in QFT-Plus supernatants.FindingsA monofunctional mycobacterial antigen-specific TNF+ CD4+ effector memory (CCR7-CD45RA-) T-cell response at 6–10 weeks of age was associated with Mtb infection at 14 months of age as measured by ESAT-6/CFP-10-specific IFN-γ and non-IFN-γ responses (Odds Ratio 2.26; Confidence Interval 1.27–4.15; P = 0.006). Mycobacterial antigen-specific polyfunctional effector memory Th1 responses at 6–10 weeks positively correlated with TST induration in infants without evidence of Mtb infection at 14 months, an association which was diminished by INH therapy.InterpretationInduction of monofunctional TNF+ CD4+ effector memory T-cell responses may be detrimental in TB vaccine development. This study also provides mechanistic insight into the association of BCG-induced immune responses with TST induration and further evidence that TST-based diagnoses of Mtb infection in infants are imprecise.FundingThrasher Research Fund.

Blue Skies research is essential for ending the Tuberculosis pandemic and advancing a personalized medicine approach for holistic management of Respiratory Tract infections.

ObjectivesInvestments into ‘Blue Skies’ fundamental TB research in low- and middle-income countries (LMICs) have not been forthcoming. We highlight why blue skies research will be essential for achieving global TB control and eradicating TB.MethodsWe review the historical background to early TB discovery research and give examples of where investments into basic science and fundamental ‘blue skies research’ are delivering novel data and approaches to advance diagnosis, management and holistic care for patients with active and latent TB infection.FindingsThe COVID-19 pandemic has shown that making available adequate funding for priority investments into ‘Blue skies research’ to delineate scientific understanding of a new infectious diseases threat to global health security can lead to rapid development and rollout of new diagnostic platforms, treatments, and vaccines. Several advances in new TB diagnostics, new treatments and vaccine development are underpinned by basic science research.ConclusionsBlue Skies research is required to pave the way for a personalized medicine approach for management of TB and other Respiratory Tract Infections and preventing long-term functional disability. Transfer of skills and resources by wealthier nations is required to empower researchers in LMICs countries to engage in and lead Blue Skies research.

Tuberculosis Vaccines: An Update of Recent and Ongoing Clinical Trials

TB remains a global health challenge and, until now, only one licensed vaccine (the BCG vaccine) is available. The main goal of this work is to assess the progress in the development of new TB vaccines and highlight the research in nanovaccines. A review was conducted using a methodology with the appropriate keywords and inclusion and exclusion criteria. The search revealed 37 clinical trials that were further reviewed. The results available have reported good immunogenicity and safety profiles for the vaccines under investigation. Over the last five years, the vaccines, VPM1002 and Vaccae, have moved ahead to phase III clinical trials, with the remaining candidate vaccines progressing in phase I and II clinical trials. RUTI and ID93+GLA-SE involve the use of nanoparticles. This strategy seems promising to improve the delivery, efficacy, cost, and storage conditions of the existing TB vaccines. In conclusion, the use of nanovaccines may be an option for both prevention and treatment. However, further studies are necessary for the development of novel TB vaccines.

Mycobacterium tuberculosis Specific Protein Rv1509 Evokes Efficient Innate and Adaptive Immune Response Indicative of Protective Th1 Immune Signature.

Dissecting the function(s) of proteins present exclusively in Mycobacterium tuberculosis (M.tb) will provide important clues regarding the role of these proteins in mycobacterial pathogenesis. Using extensive computational approaches, we shortlisted ORFs/proteins unique to M.tb among 13 different species of mycobacteria and identified a hypothetical protein Rv1509 as a ‘signature protein’ of M.tb. This unique protein was found to be present only in M.tb and absent in all other mycobacterial species, including BCG. In silico analysis identified numerous putative T cell and B cell epitopes in Rv1509. Initial in vitro experiments using innate immune cells demonstrated Rv1509 to be immunogenic with potential to modulate innate immune responses. Macrophages treated with Rv1509 exhibited higher activation status along with substantial release of pro-inflammatory cytokines. Besides, Rv1509 protein boosts dendritic cell maturation by increasing the expression of activation markers such as CD80, HLA-DR and decreasing DC-SIGN expression and this interaction was mediated by innate immune receptor TLR2. Further, in vivo experiments in mice demonstrated that Rv1509 protein promotes the expansion of multifunctional CD4+ and CD8+T cells and induces effector memory response along with evoking a canonical Th1 type of immune response. Rv1509 also induces substantial B cell response as revealed by increased IgG reactivity in sera of immunized animals. This allowed us to demonstrate the diagnostic efficacy of this protein in sera of human TB patients compared to the healthy controls. Taken together, our results reveal that Rv1509 signature protein has immunomodulatory functions evoking immunological memory response with possible implications in serodiagnosis and TB vaccine development.

Recovering from the Impact of the Covid-19 Pandemic and Accelerating to Achieving the United Nations General Assembly Tuberculosis Targets

In 2020, the novel COVID-19 pandemic replaced TB as the world’s top cause of death from an infectious disease. The October 21, 2020 the UN Secretary-General report on progress towards implementation of the UNHLM political declaration on TB stresses that although high-level commitments and targets had galvanized global and national progress towards ending TB, urgent and more ambitious investments and actions were required, especially in lieu of the COVID-19 pandemic where associated public health measures and travel restrictions, have disrupted health services universally. The report sets out 10 priority recommendations to get the world on track to reach agreed targets by 2022. Political commitment is more critical than ever. COVID-19 diagnostic and vaccination health services need to be aligned to TB services with active early case finding in communities, engaging the private sector care providers and mitigation of fear and stigma. Healthcare staff and community workers and leaders need to be provided with COVID-19 vaccination and personal protective equipment. The UNHLM declaration committed to mobilize 15 billion USD per annum for TB, of which 13 billion USD is for TB care and 2 billion USD per annum for TB R&D. The Global Fund needs to increase funding for TB. Learning from the unprecedented speed of COVID-19 vaccine development, fastracking development and evaluation of TB vaccines is essential. World leaders need to urgently address and reverse the socio-economic consequences of the COVID-19 pandemic and these will determine to what extent they will impact on achieving TB targets.

The TB vaccine development pathway – An innovative approach to accelerating global TB vaccine development

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.

Human leukocyte antigen associations with protection against tuberculosis infection and disease in human immunodeficiency virus-1 infected individuals, despite household tuberculosis exposure and immune suppression

BackgroundTo determine the association of human leukocyte antigen (HLA) alleles as correlates of risk for and protection against tuberculin skin test (TST) positivity and active TB disease amongst HIV-infected adults. MethodsGenomic DNA was extracted from 754 HIV-infected adults whole-blood. HLA-A, -B, -C and -DRB1 loci were genotyped by next generation sequencing methods. HLA alleles were analysed by the presence/absence of TST immune conversion and active TB disease and further stratified by exposure to a household TB contact, CD4+ T-cell count and, for active TB disease, TST-positivity. ResultsHLA-A*29:11 and - B*45:01/07 were associated with TST-positivity, while HLA-A*24:02, -A*29:02 and -B*15:16 with TST-negativity. In participants with a household TB contact, HLA-A*66:01, -A*68:02 and -B*49:01 were associated with TST-negativity. For TB disease, HLA-B*41:01, -C*06:02, -DRB1*04:01 and -DRB1*15:01 were associated with susceptibility, while HLA-B*07:02 and -DRB1*11:01 were protective, even for CD4+ T-cell count <350 cells/mm3. For initial TST-positivity and subsequent TB disease, HLA-A*01:01 and -DRB1*11:01 conveyed protection including for those with CD4+ T-cell count <350 cells/mm3. ConclusionSeveral HLA alleles are noted as correlates of TB infection, risk and natural protection in HIV-infected individuals. HLA associations may enable risk stratification of those with HIV infection. Protective alleles may assist in future TB vaccine development.

Emerging patterns of regulatory T cell function in tuberculosis.

Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infectious agent and has significant implications for global health. A major hurdle in the development of effective TB vaccines and therapies is the absence of defined immune-correlates of protection. In this context, the role of regulatory T cells (Treg ), which are essential for maintaining immune homeostasis, is even less understood. This review aims to address this knowledge gap by providing an overview of the emerging patterns of Treg function in TB. Increasing evidence from studies, both in animal models of infection and TB patients, points to the fact the role of Tregs in TB is dependent on disease stage. While Tregs might expand and delay the appearance of protective responses in the early stages of infection, their role in the chronic phase perhaps is to counter-regulate excessive inflammation. New data highlight that this important homeostatic role of Tregs in the chronic phase of TB may be compromised by the expansion of activated human leucocyte antigen D-related (HLA-DR)+ CD4+ suppression-resistant effector T cells. This review provides a comprehensive and critical analysis of the key features of Treg cells in TB; highlights the importance of a balanced immune response as being important in TB and discusses the importance of probing not just Treg frequency but also qualitative aspects of Treg function as part of a comprehensive search for novel TB treatments.

Renewing the Fight Against TB with an Old Vaccine

Prevention of pulmonary tuberculosis by vaccination has proven an elusive goal. In a recent study, Darrah etal. show that prevention of infection and disease can be achieved in non-human primates by intravenous administration of the century-old vaccine BCG. This finding heralds a step-change in the approach to TB vaccine development.

Clinical Development of New TB Vaccines: Recent Advances and Next Steps.

Mycobacterium tuberculosis (Mtb) kills more people worldwide than any single infectious pathogen, yet the only vaccine licensed against tuberculosis, Bacille Calmette Guerin (BCG) is approaching its centenary. Two recent advances in clinical tuberculosis vaccine development have invigorated the field. BCG revaccination of interferon-gamma release assay (IGRA) negative adolescents provided 45% protection against sustained Mtb infection defined by IGRA conversion; and the protein-subunit vaccine M72/AS01E provided 50% protection against progression from Mtb infection to tuberculosis disease in IGRA-positive adults. These findings provide encouraging evidence for pre-exposure and post-exposure approaches to vaccination against tuberculosis, both of which may be necessary to rapidly interrupt the cycle of Mtb transmission and sustain long-term impact on global tuberculosis control. New trials are needed to demonstrate efficacy of M72/AS01E with greater precision, in a wider age range, in diverse epidemic settings, and in populations that include Mtb-uninfected and HIV-infected persons. Modeling the impact of mass campaigns with M72/AS01E and other fast-follower vaccine candidates will be crucial to make the use case and demonstrate public health value for TB endemic countries. The size and scope of the next generation of efficacy trials, and the need to expand and accelerate the existing clinical development pipeline, will require public and private consortium funding and concerted political will.

Cloning and expression of recombinant protein CFP21 from Mycobacterium tuberculosis as a tuberculosis vaccine candidate

Increased resistance to TB drugs, may render vaccine development a more effective approach to stop or reduce TB epidemics. The antigen Culture Filtrat Protein Filtrat 21 (CPF21) is an immudominant protein encoded in RD 2 region of the Mycobacterium tuberculosis genome, capable of obtaining a strong hypersensitivity reaction and to induce very high interferon-gamma (IFN-γ) responses in patients with tuberculosis. In order to construct the recombinant plasmid pGEM-T Easy-CFP21 and express it in E. coli BL21, the CFP21 gene was amplified from M. tuberculosis H37Rv genomic DNA using PCR in vitro, and inserted into the pGEM-T Easy cloning vector. The recombinant plasmid was then transformed into E. coli JM109, followed by plasmid extraction, PCR amplification, and DNA sequencing. The correct recombinant CFP21 gene was subcloned into expression vector pGEX-2TK and transformed into E. coli BL21 strain. The white recombinant colony was selected, cultured, induced with 50 µM IPTG, and identified using SDS-PAGE electrophoresis method. These results demonstrated that CFP21 gene has been constructed and expressed successfully. The molecular weight was about 47 kDa as the fusion protein GST-CFP21 and expressed as insoluble protein. In conclusion, the target gene CFP21 has been cloned into host E. coli BL-21 strain and expressed successfully. In the future, the purified recombinant fusion protein GST-CFP21 paves the way for TB diagnosis and vaccine development.

PROTECTIVE EFFECT INDUCED BY THE NEW SUBUNIT TUBERCULOSIS VACCINE WHEN USED AS A BCG BOOST IS ASSOCIATED WITH INHIBITION OF MYCOBACTERIAL DISSEMINATION

Since 1924, BCG vaccine is used to protect children from the most severe forms of tuberculosis. At the same time, the protective effect of BCG in adults is variable. The potential for revaccination with live vaccine is further limited by the rapid spread of HIV infection. The early-secreted Mycobacterium tuberculosis proteins have been used extensively in TB vaccine development, due to their high immunogenicity and have shown protective effect in animal models. The aim of our study was to evaluate the opportunity to increase the anti-TB resistance in experimental animals by re-vaccination with a new subunit vaccine preparation following primary immunization with BCG. To perform such boost vaccination, we used a combination of the Ag85B-TB10.4-FliC chimeric protein, and the plasmid DNA encoding Ag85A antigen. Efficiency of the boost vaccination was evaluated in a model of M. tuberculosis H37Rv aerosol infection of C57BL / 6 laboratory mice, either in the intact animals, or those vaccinated with BCG only, or BCG followed by revaccination with the test vaccine. The data concerning mycobacteria outgrowth from the organs, and life-span of animals after infection were subject to comparative analysis. We have demonstrated that additional boost vaccination with the vaccine under study, as compared with conventional BCG vaccination, leads to further inhibition of mycobacteria dissemination from the site of infection, and significantly prolonged survival of infected animals.

Does the Development of Vaccines Advance Solutions for Tuberculosis?

Mycobacterium tuberculosis (Mtb) is considered as one of the most efficacious human pathogens. The global mortality rate of TB stands at approximately 2 million, while about 8 to 10 million active new cases are documented yearly. It is, therefore, a priority to develop vaccines that will prevent active TB. The vaccines currently used for the management of TB can only proffer a certain level of protection against meningitis, TB, and other forms of disseminated TB in children; however, their effectiveness against pulmonary TB varies and cannot provide life-long protective immunity. Based on these reasons, more efforts are channeled towards the development of new TB vaccines. During the development of TB vaccines, a major challenge has always been the lack of diversity in both the antigens contained in TB vaccines and the immune responses of the TB sufferers. Current efforts are channeled on widening both the range of antigens selection and the range of immune response elicited by the vaccines. The past two decades witnessed a significant progress in the development of TB vaccines; some of the discovered TB vaccines have recently even completed the third phase (phase III) of a clinical trial. The objectives of this article are to discuss the recent progress in the development of new vaccines against TB; to provide an insight on the mechanism of vaccine-mediated specific immune response stimulation, and to debate on the interaction between vaccines and global interventions to end TB.

Research and development of new tuberculosis vaccines: a review.

Tuberculosis kills more people worldwide than any other single infectious disease agent, a threat made more dire by the spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb). Development of new vaccines capable of preventing TB disease and new Mtb infection are an essential component of the strategy to combat the TB epidemic. Accordingly, the WHO considers the development of new TB vaccines a major public health priority. In October 2017, the WHO convened a consultation with global leaders in the TB vaccine development field to emphasize the WHO commitment to this effort and to facilitate creative approaches to the discovery and development of TB vaccine candidates. This review summarizes the presentations at this consultation, updated with scientific literature references, and includes discussions of the public health need for a TB vaccine; the status of efforts to develop vaccines to replace or potentiate BCG in infants and develop new TB vaccines for adolescents and adults; strategies being employed to diversify vaccine platforms; and new animal models being developed to facilitate TB vaccine development. A perspective on the status of these efforts from the major funders and organizational contributors also is included. This presentation highlights the extraordinary progress being made to develop new TB vaccines and provided a clear picture of the exciting development pathways that are being explored.

Mycobacterial Lipoprotein Z Triggers Efficient Innate and Adaptive Immunity for Protection Against Mycobacterium tuberculosis Infection.

Mycobacterial lipoproteins are considered to be involved in both virulence and immunoregulatory processes during Mycobacterium tuberculosis (M.tb) infection. In our previous investigations on the immunoreactivity of more than 30 M.tb proteins in active TB patients, we identified mycobacterial lipoprotein Z (LppZ) as one of the most immune dominant antigens. How LppZ triggers immune responses is still unclear. In this study, we analyzed LppZ-mediated innate and adaptive immunity using a murine air pouch model and an M.tb infection model, respectively. We found that LppZ could not only recruit inflammatory cells but also induce the production of proinflammatory cytokines inside the pouches. LppZ could also induce strong Th1 responses following immunization and confer protection against challenge with M.tb virulent strain H37Rv at a similar level to BCG vaccination but with less pathological damage in the lungs. Furthermore, we revealed the presence of LppZ-specific functional CD4+ T cells in the lungs of the challenged mice that were capable of secreting double or triple cytokines, including IFN-γ, IL-2, and TNF-α. Our study thus demonstrates that LppZ is of strong immunogenicity during M.tb infection in both humans and mice and has the ability to trigger effective innate and cellular immunity. Considering the limitations of candidate antigens in the pipeline of TB vaccine development, LppZ-mediated immune protection against M.tb challenge in the mouse model implies its potential application in vaccine development.

Research and development of new tuberculosis vaccines: a review.

Tuberculosis kills more people worldwide than any other single infectious disease agent, a threat made more dire by the spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb). Development of new vaccines capable of preventing TB disease and new Mtb infection are an essential component of the strategy to combat the TB epidemic. Accordingly, the WHO considers the development of new TB vaccines a major public health priority. In October 2017, the WHO convened a consultation with global leaders in the TB vaccine development field to emphasize the WHO commitment to this effort and to facilitate creative approaches to the discovery and development of TB vaccine candidates. This review summarizes the presentations at this consultation, updated with scientific literature references, and includes discussions of the public health need for a TB vaccine; the status of efforts to develop vaccines to replace or potentiate BCG in infants and develop new TB vaccines for adolescents and adults; strategies being employed to diversify vaccine platforms; and new animal models being developed to facilitate TB vaccine development. A perspective on the status of these efforts from the major funders and organizational contributors also is included. This presentation highlights the extraordinary progress being made to develop new TB vaccines and provided a clear picture of the exciting development pathways that are being explored.

Mycobacterium tuberculosis Protein Rv3841 Activates Dendritic Cells and Contributes to a T Helper 1 Immune Response.

The attenuated vaccine Mycobacterium bovis BCG (Bacille Calmette Guerin) has limited protective efficacy against TB. The development of more effective TB vaccines has focused on the mycobacterial antigens that cause strong T helper 1 (Th1) responses. Mtb protein Rv3841 (bacterioferritin B; BfrB) is known to play a crucial role in the growth of Mtb. Nonetheless, it is unclear whether Rv3841 can induce protective immunity against Mtb. Here, we studied the action of Rv3841 in maturation of dendritic cells (DCs) and its engagement in the development of T-cell immunity. We found that Rv3841 functionally activated DCs by upregulating costimulatory molecules and increased secretion of proinflammatory cytokines. Activation of DCs by Rv3841 was mediated by Toll-like receptor 4 (TLR4), followed by triggering of mitogen-activated protein kinase and nuclear factor-κB signaling pathways. In addition, Rv3841-matured DCs effectively proliferated and polarized Th1 immune response of naïve CD4+ and CD8+ T-cells. Moreover, Rv3841 specifically caused the expansion of CD4+CD44highCD62Llow T-cells from Mtb-infected mice; besides, the T-cells activated by Rv3841-matured DCs inhibited intracellular mycobacterial growth. Our data suggest that Rv3841 induces DC maturation and protective immune responses, a finding that may provide candidate of effective TB vaccines.

PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+ T cell transcriptomal molecular signatures

Protective efficacy of Bacillus Calmette-Guérin (BCG) may be affected by the methods and routes of vaccine administration. We have studied the safety and immunogenicity of oral (PO) and/or intradermal (ID) administration of BCG in healthy human subjects. No major safety concerns were detected in the 68 healthy adults vaccinated with PO and/or ID BCG. Although both PO and ID BCG could induce systemic Th1 responses capable of IFN-γ production, ID BCG more strongly induced systemic Th1 responses. In contrast, stronger mucosal responses (TB-specific secretory IgA and bronchoalveolar lavage T cells) were induced by PO BCG vaccination. To generate preliminary data comparing the early gene signatures induced by mucosal and systemic BCG vaccination, CD4+ memory T cells were isolated from subsets of BCG vaccinated subjects pre- (Day 0) and post-vaccination (Days 7 and 56), rested or stimulated with BCG infected dendritic cells, and then studied by Illumina BeadArray transcriptomal analysis. Notably, distinct gene expression profiles were identified both on Day 7 and Day 56 comparing the PO and ID BCG vaccinated groups by GSEA analysis. Future correlation analyses between specific gene expression patterns and distinct mucosal and systemic immune responses induced will be highly informative for TB vaccine development.