Tuberculosis Vaccine Development Research Articles

Mucosal and systemic antigen-specific antibody responses correlate with protection against active tuberculosis in nonhuman primates

Increasing evidence supports that antibodies can protect against active tuberculosis (TB) but knowledge of potentially protective antigens, especially in the airways, is limited. The main objective of this study was to identify antigen-specific airway and systemic immunoglobulin isotype responses associated with the outcome of controlled latent Mycobacterium tuberculosis (Mtb) infection (LTBI) versus uncontrolled infection (TB) in nonhuman primates. In a case-control design, using non-parametric group comparisons with false discovery rate adjustments, we assessed antibodies in 57 cynomolgus macaques which, following low-dose airway Mtb infection, developed either LTBI or TB. We investigated airway and systemic IgG, IgA, and IgM responses in paired bronchoalveolar lavage and plasma samples prior to, two-, and 5-6-months post Mtb infection using an antigen-unbiased approach with Mtb glycan and proteome-wide microarrays. Macaques that developed LTBI (n=36) had significantly increased airway and plasma IgA reactivities to specific arabinomannan (AM) motifs prior to Mtb infection compared to those that developed TB (n=21; p<0.01, q<0.05). Furthermore, LTBI macaques had higher plasma IgG reactivity to protein MTB32A (Rv0125) early post Mtb infection (p<0.05) and increasing airway IgG responses to some proteins over time. Our results support a protective role of pre-existing mucosal (lung) and systemic IgA to specific Mtb glycan motifs, suggesting that prior exposure to nontuberculous mycobacteria could be protective against TB. They further suggest that IgG to Mtb proteins early post infection could provide an additional protective mechanism. These findings could inform TB vaccine development strategies. NIH/NIAID AI117927, AI146329, and AI127173 to JMA.

Safety and immunogenicity of ChAdOx1 85A prime followed by MVA85A boost compared with BCG revaccination among Ugandan adolescents who received BCG at birth: a randomised, open-label trial

BCG confers reduced, variable protection against pulmonary tuberculosis. A more effective vaccine is needed. We evaluated the safety and immunogenicity of candidate regimen ChAdOx1 85A-MVA85A compared with BCG revaccination among Ugandan adolescents. After ChAdOx1 85A dose escalation and age de-escalation, we did a randomised open-label phase 2a trial among healthy adolescents aged 12-17 years, who were BCG vaccinated at birth, without evident tuberculosis exposure, in Entebbe, Uganda. Participants were randomly assigned (1:1) using a block size of 6, to ChAdOx1 85A followed by MVA85A (on day 56) or BCG (Moscow strain). Laboratory staff were masked to group assignment. Primary outcomes were solicited and unsolicited adverse events (AEs) up to day 28 and serious adverse events (SAEs) throughout the trial; and IFN-γ ELISpot response to antigen 85A (day 63 [geometric mean] and days 0-224 [area under the curve; AUC). Six adults (group 1, n=3; group 2, n=3) and six adolescents (group 3, n=3; group 4, n=3) were enrolled in the ChAdOx1 85A-only dose-escalation and age de-escalation studies (July to August, 2019). In the phase 2a trial, 60 adolescents were randomly assigned to ChAdOx1 85A-MVA85A (group 5, n=30) or BCG (group 6, n=30; December, 2019, to October, 2020). All 60 participants from groups 5 and 6 were included in the safety analysis, with 28 of 30 from group 5 (ChAdOx1 85A-MVA85A) and 29 of 30 from group 6 (BCG revaccination) analysed for immunogenicity outcomes. In the randomised trial, 60 AEs were reported among 23 (77%) of 30 participants following ChAdOx1 85A-MVA85A, 31 were systemic, with one severe event that occurred after the MVA85A boost that was rapidly self-limiting. All 30 participants in the BCG revaccination group reported at least one mild to moderate solicited AE; most were local reactions. There were no SAEs in either group. Ag85A-specific IFN-γ ELISpot responses peaked on day 63 in the ChAdOx1 85A-MVA85A group and were higher in the ChAdOx1 85A-MVA85A group compared with the BCG revaccination group (geometric mean ratio 30·59 [95% CI 17·46-53·59], p<0·0001, day 63; AUC mean difference 57 091 [95% CI 40 524-73 658], p<0·0001, days 0-224). The ChAdOx1 85A-MVA85A regimen was safe and induced stronger Ag85A-specific responses than BCG revaccination. Our findings support further development of booster tuberculosis vaccines. UK Research and Innovations and Medical Research Council. For the Swahili and Luganda translations of the abstract see Supplementary Materials section.

Vaccine development against tuberculosis before and after Covid-19.

Coronavirus disease (Covid-19) has not only shaped awareness of the impact of infectious diseases on global health. It has also provided instructive lessons for better prevention strategies against new and current infectious diseases of major importance. Tuberculosis (TB) is a major current health threat caused by Mycobacterium tuberculosis (Mtb) which has claimed more lives than any other pathogen over the last few centuries. Hence, better intervention measures, notably novel vaccines, are urgently needed to accomplish the goal of the World Health Organization to end TB by 2030. This article describes how the research and development of TB vaccines can benefit from recent developments in the Covid-19 vaccine pipeline from research to clinical development and outlines how the field of TB research can pursue its own approaches. It begins with a brief discussion of major vaccine platforms in general terms followed by a short description of the most widely applied Covid-19 vaccines. Next, different vaccination regimes and particular hurdles for TB vaccine research and development are described. This specifically considers the complex immune mechanisms underlying protection and pathology in TB which involve innate as well as acquired immune mechanisms and strongly depend on fine tuning the response. A brief description of the TB vaccine candidates that have entered clinical trials follows. Finally, it discusses how experiences from Covid-19 vaccine research, development, and rollout can and have been applied to the TB vaccine pipeline, emphasizing similarities and dissimilarities.

Recent advance in the development of tuberculosis vaccines in clinical trials and virus-like particle-based vaccine candidates.

Tuberculosis (TB) remains a serious public health threat around the world. An effective vaccine is urgently required for cost-effective, long-term control of TB. However, the only licensed vaccine Bacillus Calmette-Guerin (BCG) is limited to prevent TB for its highly variable efficacy. Substantial progress has been made in research and development (R&D) of TB vaccines in the past decades, and a dozen vaccine candidates, including live attenuated mycobacterial vaccines, killed mycobacterial vaccines, adjuvanted subunit vaccines, viral vector vaccines, and messenger RNA (mRNA) vaccines were developed in clinical trials to date. Nevertheless, many challenges to the successful authorization for the use and deployment of an effective tuberculosis vaccine remain. Therefore, it is still necessary and urgent to continue exploring new vaccine construction approaches. Virus-like particles (VLPs) present excellent prospects in the field of vaccine development because of their helpful immunological features such as being safe templates without containing viral nucleic acid, repetitive surface geometry, conformational epitopes similar to natural viruses, and enhancing both innate and adaptive immune responses. The marketization process of VLP vaccines has never stopped despite VLP vaccines face several shortcomings such as their complex and slow development process and high production cost, and several VLP-based vaccines, including vaccines against Human papillomavirus (HPV), Hepatitis B Virus (HBV) and malaria, are successfully licensed for use at the market. In this review, we provide an update on the current progress regarding the development of TB vaccines in clinical trials and seek to give an overview of VLP-based TB vaccine candidates.

Conference report: WHO meeting summary on mRNA-based tuberculosis vaccine development

Tuberculosis (TB) is a global health emergency. Across the globe, approximately 2 billion people are currently infected with Mycobacterium tuberculosis (Mtb), and of those, 5–10% may progress to become ill and potentially transmit the bacterium. In 2021, nearly 10.6 million people developed TB disease and 1.6 million died. There is an urgent need for accelerated development of new TB-focused interventions, in particular, improved TB vaccines. However, progress in developing highly effective TB vaccines has been slow and is chronically under-resourced. The mRNA vaccine platform may offer an opportunity to accelerate development of new TB vaccines.In April 2023, the World Health Organization convened global experts to discuss the feasibility and potential value of mRNA-based vaccines for TB. Here we report on meeting deliberations related to the current TB vaccine pipeline and potential novel antigens, the status of efforts to identify correlates of protection, potential clinical development strategies and considerations for community acceptance of new TB vaccines based on this relatively new platform. The role of industry collaborations, ethics, social science, and responsibility to the global community regarding transparency and manufacturing capacity building were discussed through expert presentations and panel sessions. The overall conclusion of the meeting is that mRNA-based vaccines constitute a potentially powerful new tool for reducing the global burden of TB.

Construction and evaluation of a novel multi-antigenic Mycobacterium tuberculosis subunit vaccine candidate BfrB-GrpE/DPC

Tuberculosis poses a significant threat to human health due to the lack of an effective vaccine. Although promising progress has been made in the development of tuberculosis vaccines, new vaccines that broaden the antigenic repertoire need to be developed to eradicate this illness. In this study, we used Mycobacterium tuberculosis ferritin BfrB and heat-shock protein GrpE to construct a novel multi-antigenic fusion protein, BfrB-GrpE (BG). BG protein was stably overexpressed in the soluble form in Escherichia coli at a high yield and purified via sequential salt fractionation and hydrophobic chromatography. Purified BG was emulsified in an adjuvant containing N, N'-dimethyl-N, N'-dioctadecylammonium bromide, polyinosinic-polycytidylic acid, and cholesterol (DPC) to construct the BG/DPC vaccine, which stimulated strong cellular and humoral immune responses in mice. Moreover, combination of BG with our previously developed vaccine, Mtb10.4-HspX (MH), containing antigens from both the proliferating and dormant stages, significantly reduced the bacterial counts in the lungs and spleens of M. tuberculosis-infected mice. Importantly, mice that received BG + MH/DPC after M. tuberculosis H37Rv infection survived slightly better (100% survival) than those that received the BCG vaccine (80% survival), although the difference was not statistically significant. Our findings can aid in the selection of antigens and optimization of vaccination regimens to improve the efficacy of tuberculosis vaccines.

Molecular detection of pre-ribosomal RNAs of Mycobacterium bovis bacille Calmette-Guérin and Mycobacterium tuberculosis to enhance pre-clinical tuberculosis drug and vaccine development

Efforts are underway globally to develop effective vaccines and drugs against M. tuberculosis (Mtb) to reduce the morbidity and mortality of tuberculosis. Improving detection of slow-growing mycobacteria could simplify and accelerate efficacy studies of vaccines and drugs in animal models and human clinical trials. Here, a real-time reverse transcription PCR (RT-PCR) assay was developed to detect pre-ribosomal RNA (pre-rRNA) of Mycobacterium bovis bacille Calmette-Guérin (BCG) and Mtb. This pre-rRNA biomarker is indicative of bacterial viability. In two different mouse models, the presence of pre-rRNA from BCG and Mtb in ex vivo tissues showed excellent agreement with slower culture-based colony-forming unit assays. The addition of a brief nutritional stimulation prior to molecular viability testing further differentiated viable but dormant mycobacteria from dead mycobacteria. This research has set the stage to evaluate pre-rRNA as a BCG and/or Mtb infection biomarker in future drug and vaccine clinical studies.

A five-antigen Esx-5a fusion delivered as a prime-boost regimen protects against M.tb challenge.

The development of tuberculosis (TB) vaccines has been hindered by the complex nature of Mycobacterium tuberculosis (M.tb) and the absence of clearly defined immune markers of protection. While Bacillus Calmette-Guerin (BCG) is currently the only licensed TB vaccine, its effectiveness diminishes in adulthood. In our previous research, we identified that boosting BCG with an intranasally administered chimpanzee adenovirus expressing the PPE15 antigen of M.tb (ChAdOx1.PPE15) improved its protection. To enhance the vaccine's efficacy, we combined PPE15 with the other three members of the Esx-5a secretion system and Ag85A into a multi-antigen construct (5Ag). Leveraging the mucosal administration safety of ChAdOx1, we targeted the site of M.tb infection to induce localized mucosal responses, while employing modified vaccinia virus (MVA) to boost systemic immune responses. The combination of these antigens resulted in enhanced BCG protection in both the lungs and spleens of vaccinated mice. These findings provide support for advancing ChAdOx1.5Ag and MVA.5Ag to the next stages of vaccine development.

Addressing mechanism bias in model-based impact forecasts of new tuberculosis vaccines

In tuberculosis (TB) vaccine development, multiple factors hinder the design and interpretation of the clinical trials used to estimate vaccine efficacy. The complex transmission chain of TB includes multiple routes to disease, making it hard to link the vaccine efficacy observed in a trial to specific protective mechanisms. Here, we present a Bayesian framework to evaluate the compatibility of different vaccine descriptions with clinical trial outcomes, unlocking impact forecasting from vaccines whose specific mechanisms of action are unknown. Applying our method to the analysis of the M72/AS01E vaccine trial -conducted on IGRA+ individuals- as a case study, we found that most plausible models for this vaccine needed to include protection against, at least, two over the three possible routes to active TB classically considered in the literature: namely, primary TB, latent TB reactivation and TB upon re-infection. Gathering new data regarding the impact of TB vaccines in various epidemiological settings would be instrumental to improve our model estimates of the underlying mechanisms.

Bridging the gaps to overcome major hurdles in the development of next-generation tuberculosis vaccines.

Although tuberculosis (TB) remains one of the leading causes of death from an infectious disease worldwide, the development of vaccines more effective than bacille Calmette-Guérin (BCG), the only licensed TB vaccine, has progressed slowly even in the context of the tremendous global impact of TB. Most vaccine candidates have been developed to strongly induce interferon-γ (IFN-γ)-producing T-helper type 1 (Th1) cell responses; however, accumulating evidence has suggested that other immune factors are required for optimal protection against Mycobacterium tuberculosis (Mtb) infection. In this review, we briefly describe the five hurdles that must be overcome to develop more effective TB vaccines, including those with various purposes and tested in recent promising clinical trials. In addition, we discuss the current knowledge gaps between preclinical experiments and clinical studies regarding peripheral versus tissue-specific immune responses, different underlying conditions of individuals, and newly emerging immune correlates of protection. Moreover, we propose how recently discovered TB risk or susceptibility factors can be better utilized as novel biomarkers for the evaluation of vaccine-induced protection to suggest more practical ways to develop advanced TB vaccines. Vaccines are the most effective tools for reducing mortality and morbidity from infectious diseases, and more advanced technologies and a greater understanding of host-pathogen interactions will provide feasibility and rationale for novel vaccine design and development.

Stressed stability and protective efficacy of lead lyophilized formulations of ID93+GLA-SE tuberculosis vaccine

With the recent exception of coronavirus disease 2019 (COVID-19), tuberculosis (TB) causes more deaths globally than any other infectious disease, and approximately 1/3 of the world's population is infected with Mycobacterium tuberculosis (Mtb). However, encouraging progress in TB vaccine development has been reported, with approximately 50% efficacy achieved in Phase 2b clinical testing of an adjuvanted subunit TB vaccine candidate. Nevertheless, current lead vaccine candidates require cold-chain transportation and storage. In addition to temperature stress, vaccines may be subject to several other stresses during storage and transport, including mechanical, photochemical, and oxidative stresses. Optimal formulations should enable vaccine configurations with enhanced stability and decreased sensitivity to physical and chemical stresses, thus reducing reliance on the cold chain and facilitating easier worldwide distribution. In this report, we describe the physicochemical stability performance of three lead thermostable formulations of the ID93 + GLA-SE TB vaccine candidate under various stress conditions. Moreover, we evaluate the impact of thermal stress on the protective efficacy of the vaccine formulations. We find that formulation composition impacts stressed stability performance, and our comprehensive evaluation enables selection of a lead single-vial lyophilized candidate containing the excipient trehalose and Tris buffer for advanced development.

Сравнительное исследование иммуногенности полноразмерной и мультиэпитопной мРНК-вакцин против M. Tuberculosis по выраженности Т-клеточного ответа у мышей

Development of the new tuberculosis vaccines that would be effective in adults is an urgent task: worldwide, the annual death toll of this disease exceeds 1.5 million. In the recent decades, the matter has been addressed in numerous studies, but none has yielded an effective vaccine so far. There are many factors to resistance against tuberculosis; this study focuses on the T-cell response, a mechanism that enables elimination of intracellular pathogens, such as M. tuberculosis. We aimed to develop an mRNA vaccine capable of triggering a pronounced T-cell response to the M. tuberculosis antigens. The in silico analysis allowed us to select epitopes of the M. tuberculosis secreted protein ESAT6 (Rv3875) and design a multi-epitope mRNA vaccine thereon. We assessed the intensity of T-cell response in mice immunized with mRNA vaccines that encode a full-length or multi-epitope antigen. The results of this study in mice show that immunization with a multi-epitope mRNA vaccine produces twice as many IFNγ-secreting splenocytes in response to specific stimulation than immunization with an mRNA vaccine encoding the full-length protein. Thus, the developed multi-epitope mRNA vaccine can be an effective M. tuberculosis prevention agent the mode of action of which involves formation of a pronounced T-cell response.

Immunogenicity and efficacy analyses of EPC002, ECA006, and EPCP009 protein subunit combinations as tuberculosis vaccine candidates

Tuberculosis (TB) is the leading cause of death from infectious diseases worldwide, and developing a new TB vaccine is a priority for TB control. Combining multiple immunodominant antigens to form a novel multicomponent vaccine with broad-spectrum antigens to induce protective immune responses is a trend in TB vaccine development. In this study, we used T-cell epitope-rich protein subunits to construct three antigenic combinations: EPC002, ECA006, and EPCP009. Fusion expression of purified protein EPC002f (CFP-10-linker-ESAT-6-linker-nPPE18), ECA006f (CFP-10-linker-ESAT-6-linker-Ag85B), and EPCP009f (CFP-10-linker-ESAT-6-linker-nPPE18-linker-nPstS1) and recombinant purified protein mixtures EPC002m (mix of CFP-10, ESAT-6, and nPPE18), ECA006m (mix of CFP-10, ESAT-6, and Ag85B), and EPCP009m (mix of CFP-10, ESAT-6, nPPE18, and nPstS1) were used as antigens, formulated with alum adjuvant, and the immunogenicity and efficacy were analyzed using immunity experiments with BALB/c mice. All protein-immunized groups elicited higher levels of humoral immunity, including IgG and IgG1. The IgG2a/IgG1 ratio of the EPCP009m-immunized group was the highest, followed by that of the EPCP009f-immunized group, which was significantly higher than the ratios of the other four groups. The multiplex microsphere-based cytokine immunoassay revealed that EPCP009f and EPCP009m induced the production of a wider range of cytokines than EPC002f, EPC002m, ECA006f, and ECA006m, which included Th1-type (IL-2, IFN-γ, TNF-α), Th2-type (IL-4, IL-6, IL-10), Th17-type (IL-17), and other proinflammatory cytokines (GM-CSF, IL-12). The enzyme-linked immunospot assays demonstrated that the EPCP009f- and EPCP009m-immunized groups had significantly higher amounts of IFN-γ than the other four groups. The in vitro mycobacterial growth inhibition assay demonstrated that EPCP009m inhibited Mycobacterium tuberculosis (Mtb) growth most strongly, followed by EPCP009f, which was significantly better than that of the other four vaccine candidates. These results indicated that EPCP009m containing four immunodominant antigens exhibited better immunogenicity and Mtb growth inhibition in vitro and may be a promising candidate vaccine for the control of TB.

Vaccines against Tuberculosis: Where Are We Now?

Tuberculosis (TB) is among the top 10 leading causes of death in low-income countries. Statistically, TB kills more than 30,000 people each week and leads to more deaths than any other infectious disease, such as acquired immunodeficiency syndrome (AIDS) and malaria. TB treatment is largely dependent on BCG vaccination and impacted by the inefficacy of drugs, absence of advanced vaccines, misdiagnosis improper treatment, and social stigma. The BCG vaccine provides partial effectiveness in demographically distinct populations and the prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB incidences demands the design of novel TB vaccines. Various strategies have been employed to design vaccines against TB, such as: (a) The protein subunit vaccine; (b) The viral vector vaccine; (c) The inactivation of whole-cell vaccine, using related mycobacteria, (d) Recombinant BCG (rBCG) expressing Mycobacterium tuberculosis (M.tb) protein or some non-essential gene deleted BCG. There are, approximately, 19 vaccine candidates in different phases of clinical trials. In this article, we review the development of TB vaccines, their status and potential in the treatment of TB. Heterologous immune responses generated by advanced vaccines will contribute to long-lasting immunity and might protect us from both drug-sensitive and drug-resistant TB. Therefore, advanced vaccine candidates need to be identified and developed to boost the human immune system against TB.

NATCON 2022 Panel discussion: “TB vaccination - Going Forward”

Vaccination is important tuberculosis (TB) preventive strategy that is essential to achieve the goals of the End TB strategy. The BCG vaccination at birth offers protection against TB in young children but not in adolescents and adults. New TB vaccines are the need of the hour. The TB vaccine development pipeline in the past years is encouraging with newer TB vaccines in clinical trials in humans. The focus of the newer TB vaccine is the prevention of infection, disease, and recurrence of TB disease. Therapeutic vaccines focus on better treatment outcomes and prevention of TB recurrence. BCG revaccination is of current interest. Novel, safe, and efficient TB vaccines that prevent TB infection and disease if introduced in 2025 could drastically reduce the rate of TB incidence. However, the development of an effective vaccine for TB is challenging. Engagement of stakeholders, mobilizing funding, and advocacy could accelerate the newer TB vaccine development process.

A Multistage Antigen Complex Epera013 Promotes Efficient and Comprehensive Immune Responses in BALB/c Mice

Tuberculosis (TB) remains a serious global health problem. Despite the widespread use of the Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine, the primary factor for the TB pandemic and deaths is adult TB, which mainly result from endogenous reactivation of latent Mycobacterium tuberculosis (MTB) infection. Improved new TB vaccines with eligible safety and long-lasting protective efficacy remains a crucial step toward the prevention and control of TB. In this study, five immunodominant antigens, including three early secreted antigens and two latency associated antigens, were used to construct a single recombinant fusion protein (Epera013f) and a protein mixture (Epera013m). When formulated with aluminum adjuvant, the two subunit vaccines Epera013m and Epera013f were administered to BALB/c mice. The humoral immune responses, cellular responses and MTB growth inhibiting capacity elicited after Epera013m and Epera013f immunization were analyzed. In the present study, we demonstrated that both the Epera013f and Epera013m were capable of inducing a considerable immune response and protective efficacy against H37Rv infection compared with BCG groups. In addition, Epera013f generated a more comprehensive and balanced immune status, including Th1, Th2 and innate immune response, over Epera013f and BCG. The multistage antigen complex Epera013f possesses considerable immunogenicity and protective efficacy against MTB infection ex vivo indicating its potential and promising applications in further TB vaccine development.

Antibodies Targeting the Cell Wall Induce Protection against Virulent Mycobacterium bovis Infection.

Accumulating evidence indicates that antibodies can protect against some intracellular pathogens. Mycobacterium bovis is an intracellular bacterium, and its cell wall (CW) is essential for its virulence and survival. However, the questions of whether antibodies play a protective role in immunity against M. bovis infection and what effects antibodies specific to the CW of M. bovis have still remain unclear. Here, we report that antibodies targeting the CW of an isolated pathogenic M. bovis strain and that of an attenuated bacillus Calmette-Guérin (BCG) strain could induce protection against virulent M. bovis infection in vitro and in vivo. Further research found that the antibody-induced protection was mainly achieved by promoting Fc gamma receptor (FcγR)-mediated phagocytosis, inhibiting bacterial intracellular growth, and enhancing the fusion of phagosomes and lysosomes, and it also depended on T cells for its efficacy. Additionally, we analyzed and characterized the B-cell receptor (BCR) repertoires of CW-immunized mice via next-generation sequencing. CW immunization stimulated BCR changes in the complementarity determining region 3 (CDR3) isotype distribution, gene usage, and somatic hypermutation. Overall, our study validates the idea that antibodies targeting the CW induce protection against virulent M. bovis infection. This study highlights the importance of antibodies targeting the CW in the defense against tuberculosis. IMPORTANCE M. bovis is the causative agent of animal tuberculosis (TB) and human TB. Research on M. bovis is of great public health significance. Currently, TB vaccines are mainly aimed at eliciting protection by enhancement of cell-mediated immunity, and there are few studies on protective antibodies. This is the first report of protective antibodies against M. bovis infection, and the antibodies had both preventive and even therapeutic effects in an M. bovis infection mouse model. Additionally, we reveal the relationship between CDR3 gene diversity and the immune characteristics of the antibodies. These results will provide valuable advice for the rational development of TB vaccines.

A Summary on Tuberculosis Vaccine Development-Where to Go?

Tuberculosis (TB) is an old infectious disease caused by Mycobacterium tuberculosis infection. Vaccination is the most effective way to prevent and control TB. However, there is relatively little literature that systematically analyzes the progress of new TB vaccine research from a bibliometric perspective. This study was conducted to examine the development of TB vaccines over the past 20 years and to identify research priorities and directions for the future. The Science Citation Index Expanded (SCI-E) of the Web of Science Core Collection (WOSCC) database was selected to search the literature related to TB vaccines. The countries, institutions, authors, journals, references, and keywords of each publication were analyzed and visualized using the VOSviewer, CiteSpace, and Bibliometrix software. Furthermore, GraphPad Prism and Microsoft Excel 365 were also used for statistical analysis. As of 20 October 2022, 7960 publications related to TB vaccines were identified with 288,478 citations. The United States of America (USA) accounted for the largest share (2658, 33.40%), followed by the United Kingdom (UK, 1301, 16.34%), and China (685, 8.6%). Regarding affiliations, the University of London had the most publications (427) and shared the highest H-index (76) with the Statens Serum Institut of Denmark. In terms of the number of articles for the journals and authors, the journal Vaccine ranked first with 629 articles. Professor Peter Anderssen has published the highest number of papers (160). The burst keywords and thematic maps analysis showed that future trends in TB vaccine development would focus on exploring the interaction mechanisms between M. tuberculosis and the host. The number of publications on TB vaccines has grown over the past two decades. Developed countries play a significant role in TB vaccine research, and developing countries are fast catching up. We believe that future research will be aimed at understanding the fine molecular mechanisms of host-pathogen interaction, leading to the development of better TB vaccines.

A Structural View at Vaccine Development against M. tuberculosis.

Tuberculosis (TB) is still the leading global cause of death from an infectious bacterial agent. Limiting tuberculosis epidemic spread is therefore an urgent global public health priority. As stated by the WHO, to stop the spread of the disease we need a new vaccine, with better coverage than the current Mycobacterium bovis BCG vaccine. This vaccine was first used in 1921 and, since then, there are still no new licensed tuberculosis vaccines. However, there is extremely active research in the field, with a steep acceleration in the past decades, due to the advance of technologies and more rational vaccine design strategies. This review aims to gather latest updates in vaccine development in the various clinical phases and to underline the contribution of Structural Vaccinology (SV) to the development of safer and effective antigens. In particular, SV and the development of vaccine adjuvants is making the use of subunit vaccines, which are the safest albeit the less antigenic ones, an achievable goal. Indeed, subunit vaccines overcome safety concerns but need to be rationally re-engineered to enhance their immunostimulating effects. The larger availability of antigen structural information as well as a better understanding of the complex host immune response to TB infection is a strong premise for a further acceleration of TB vaccine development.

Proteome Profile Changes Induced by Heterologous Overexpression of Mycobacterium tuberculosis-Derived Antigens PstS-1 (Rv0934) and Ag85B (Rv1886c) in Mycobacterium microti.

The development of new tuberculosis vaccines remains a global priority, and recombinant vaccines are a frequently investigated option. These vaccines follow a molecular strategy that may enhance protective efficacy. However, their functional differences, particularly with respect to glycosylation, remain unknown. Recent studies have shown that glycosylation plays a key role in the host-pathogen interactions during immune recognition. The aim of this study was to determine the differences in the glycosylation profiles of two recombinant strains of Mycobacterium microti, overexpressing Ag85B (Rv1886c) and PstS-1 (Rv0934) antigens of M. tuberculosis. For each strain, the glycosylation profile was determined by Western blotting with lectins. The results showed the presence of mannosylated proteins and evidence of linked sialic acid proteins. Interestingly, different proteome and glycoproteome profiles were observed between the two recombinant strains and the wild-type strain. We have shown here that the construction of the recombinant strains of M. microti has altered the proteome and glycosylation profiles of these strains, leading us to ask what impact these changes might have on the immune response.