What's Old and New in Tuberculosis Vaccines for Children.

TB is now the leading, global cause of death due to a single infectious microbe. To achieve the End TB vision of reducing TB by 90% by 2035 we will need new interventions. The objectives of this manuscript are to summarize the status of the clinical TB vaccine pipeline; to assess the challenges facing the TB development field; and to discuss some of the key strategies being embraced by the field to overcome these challenges. Currently, 8 of the 13 vaccines in clinical development are subunit vaccines; 6 of these contain or express either Ag85A or Ag85B proteins. A major challenge to TB vaccine development is the lack of diversity in both the antigens included in TB vaccines, and the immune responses elicited by TB vaccine candidates. Both will need to be expanded to maximise the potential for developing a successful candidate by 2025. Current research efforts are focused on broadening both antigen selection and the range of vaccine-mediated immune responses. Previous and ongoing TB vaccine efficacy trials have built capacity, generated high quality data on TB incidence and prevalence, and provided insight into immune correlates of risk of TB disease. These gains will enable the design of better TB vaccines and, importantly, move these vaccines into efficacy trials more rapidly and at a lower cost than was possible for previous TB vaccine candidates.

Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.

ObjectivesTuberculosis (TB) is the leading cause of death worldwide before the corona virus pandemic, but the only licensed vaccine to date is Bacillus Calmette–Guérin (BCG). This manuscript aims to introduce the current status and trends of clinical research on TB vaccines, one of the most difficult vaccines to develop.MethodsTo identify the current status of clinical development, we reviewed the literature on TB vaccine candidates currently in the clinical pipeline and the World Health Organization (WHO) reports on the introduction of new vaccine developments.ResultsAs of September 2024, 15 TB vaccines candidates are in the clinical pipeline. Across vaccine platforms, six whole-cell, five recombinant protein, two viral vector-based, and two mRNA vaccines are in clinical development, with the largest number of candidates being whole-cell-based vaccines. As of 2024, two mRNA vaccines are also in Phase 1 clinical trials. WHO predicts that a new TB vaccine will be available within five years. The recombinant protein-based M72/AS01E vaccine has been mentioned as a potential vaccine, and is currently recruiting subjects for a Phase 3 clinical trial. In addition, recombinant protein-based GemTBvac and whole cell-based MIP, MTBVAC, and VPM1002 are in Phase 3 clinical trials.ConclusionsWhile several platform-based TB vaccine candidates are in clinical trials; however, the antigens contained in these candidates are often redundant and limited. To diversify the TB vaccine clinical pipeline, it is necessary to continue research to identify new antigens, the development of preclinical animal models for efficacy evaluation, and the identification of valid endpoints through the analysis of clinical trial results are necessary.

Pediatric tuberculosis (TB) is an underappreciated problem and accounts for 10 % of all TB deaths worldwide. Children are highly susceptible to infection with Mycobacterium tuberculosis and interrupting TB spread would require the development of effective strategies to control TB transmission in pediatric populations. The current vaccine for TB, M. bovis Bacille Calmette-Guérin (BCG), can afford some level of protection against TB meningitis and severe forms of disseminated TB in children; however, its efficacy against pulmonary TB is variable and the vaccine does not afford life-long protective immunity. For these reasons there is considerable interest in the development of new vaccines to control TB in children. Multiple vaccine strategies are being assessed and include recombinant forms of the existing BCG vaccine, protein or viral candidates designed to boost BCG-induced immunity, or live attenuated forms of M. tuberculosis. A number of these candidates have entered clinical trials; however, no vaccine has shown improved protective efficacy compared to BCG in humans. The current challenge is to identify the most suitable candidates to progress from early to late stage clinical trials, in order to deliver a vaccine that can control and hopefully eliminate the global threat of TB.

DNA encoding a single mycobacterial antigen protects against leprosy infection

Evaluation of: Ota MO, Odutola AA, Owiafe PK et al. Immunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infants. Sci. Trans. Med. 3(88), 88ra56 (2011).Several new TB vaccines are currently undergoing clinical trials. Among the most promising is a vaccine based upon the modified vaccinia virus Ankara-expressing mycobacterial antigen 85A (MVA85A). Given the widespread use of the current TB vaccine, BCG, many of the new TB vaccines are being tested for their ability to boost BCG-induced immunity. The introduction of a new TB vaccine into routine use would be facilitated by its coadministration with other vaccines as a part of the WHO’s Expanded Program on Immunization (EPI). In the article under review the authors tested the immunogenicity of MVA85A given alone or in combination with EPI vaccines to infants in The Gambia. Antigen 85A-specific production of IFN-γ by peripheral blood cells was reduced significantly in infants coimmunized with EPI vaccines compared with infants who received the MVA85A vaccine alone. This study highlights a potentially important issue, which should be addressed prior to the introduction of new TB vaccines and, perhaps, other vaccines that require the induction of a so-called Type 1 T-cell-mediated immune response.

The failure of current Mycobacterium bovis bacille Calmette–Guérin (BCG) vaccines, given to neonates to protect against adult tuberculosis and the risk of using these live vaccines in HIV-infected infants, has emphasized the need for generating new, more efficacious and safer replacement vaccines. With the availability of genetic techniques for constructing recombinant BCG (rBCG) strains containing well-defined gene deletions or insertions, new vaccine candidates are under evaluation at both the preclinical and clinical stages of development. Since most BCG vaccines in use today were evaluated in clinical trials decades ago and are produced by outdated processes, the development of new BCG vaccines offers a number of advantages that include a modern well-defined manufacturing process along with state-of-the-art evaluation of safety and efficacy in target populations. We provide a description of the preclinical development of two novel rBCGs, VPM1002 that was constructed by adding a modified hly gene coding for the protein listeriolysin O (LLO) from Listeria monocytogenes and AERAS-422, which carries a modified pfoA gene coding for the protein perfringolysin O (PFO) from Clostridium perfringens, and three genes from Mycobacterium tuberculosis. Novel approaches like these should be helpful in generating stable and effective rBCG vaccine candidates that can be better characterized than traditional BCG vaccines.

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.

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.

Recently, two Phase 2B tuberculosis vaccine trials reported positive efficacy results in adolescents and adults. However, experience in vaccinating these age groups is limited. We identified potential implementation strategies for the M72/AS01E vaccination and BCG-revaccination-like candidates and explored their acceptability and feasibility. We conducted in-depth semi-structured interviews among key decision makers to identify implementation strategies and target groups in South Africa, India, and China. Thematic and deductive analysis using a coding framework were used to identify themes across and within settings. In all three countries there was interest in novel TB vaccines, with school-attending adolescents named as a likely target group. In China and India, older people were also identified as a target group. Routine vaccination was preferred in all countries due to stigma and logistical issues with targeted mass campaigns. Perceived benefits for implementation of M72/AS01E were the likely efficacy in individuals with Mycobacterium tuberculosis (Mtb) infection and efficacy for people living with HIV. Perceived challenges for M72/AS01E included the infrastructure and the two-dose regimen required. Stakeholders valued the familiarity of BCG but were concerned about the adverse effects in people living with HIV, a particular concern in South Africa. Implementation challenges and opportunities were identified in all three countries. Our study provides crucial information for implementing novel TB vaccines in specific target groups and on country specific acceptability and feasibility. Key groups for vaccine implementation in these settings were identified, and should be included in clinical trials and implementation planning.

Tuberculosis (TB) is the most common opportunistic disease and a potentially fatal complication among immunocompromised individuals infected with human immunodeficiency virus (HIV). Effective vaccination against TB in persons with HIV has been considered unlikely because of the central role that CD4 cells play in controlling tuberculous infections. Here we show that the vaccination of CD8(-/-) mice with a TB DNA vaccine cocktail did not significantly enhance protective responses to a Mycobacterium tuberculosis infection. In contrast, immunization with a DNA vaccine cocktail or with the current TB vaccine, Mycobacterium bovis BCG, induced considerable antituberculosis protective immunity in immune-deficient mice lacking CD4 cells. In vaccinated CD4(-/-) animals, substantially reduced bacterial burdens in organs and much improved lung pathology were seen 1 month after an aerogenic M. tuberculosis challenge. Importantly, the postchallenge mean times to death of vaccinated CD4(-/-) mice were significantly extended (mean with DNA cocktail, 172 +/- 7 days; mean with BCG, 156 +/- 22 days) compared to that of naïve CD4(-/-) mice (33 +/- 6 days). Furthermore, the treatment of DNA-vaccinated CD4(-/-) mice with an anti-CD8 or anti-gamma interferon (IFN-gamma) antibody significantly reduced the effect of immunization, and neither IFN-gamma(-/-) nor tumor necrosis factor receptor-deficient mice were protected by DNA immunization; therefore, the primary vaccine-induced protective mechanism in these immune-deficient mice likely involves the secretion of cytokines from activated CD8 cells. The substantial CD8-mediated protective immunity that was generated in the absence of CD4 cells suggests that it may be possible to develop effective TB vaccines for use in HIV-infected populations.

Recent mouse models and vaccine candidates for preventing chronic/latent tuberculosis infection and its reactivation

The vision of the South African Tuberculosis Vaccine Initiative (SATVI) (www.satvi.uct.ac.za) is 'A World Without TB' and our mission is 'Innovative and high-quality TB vaccine research in Africa, to impact the global epidemic'. Over the last 10 years, our focus has been twofold: first, clinical trials of BCG and of new candidate vaccines, and second, complementary research that addresses critical questions in TB vaccine development. SATVI is now widely regarded as the leading TB vaccine clinical research site in the world.

Introduction: The coronavirus disease (COVID)-19 pandemic has affected nearly every facet of life, including clinical research, and has had an adverse and extensive impact on clinical trials including pediatric vaccine trials. Across the globe, countries implemented a variety of restrictions to people’s everyday lives, which have substantially impacted the ability to conduct pediatric vaccine trials. Objectives: The objectives of the study were to assess the impact of the COVID-19 pandemic on enrollment and follow-up of clinical trial participants in pediatric vaccine clinical trials and simultaneously to explore various strategies used for overcoming these challenges during the COVID-19 pandemic period. Materials and Methods: Data of 10 pediatric vaccine clinical trials were obtained from the clinical trial records of the Clinical Research Unit. The number of subjects enrolled, number of study dropouts, protocol deviations, and reasons for participant dropout/deviations were recorded from these pediatric vaccine clinical trials carried out before and during the COVID-19 pandemic period from March to December 2020. These metrics were then compared with their counterparts recorded during our study to statistically assess the impact of the COVID-19 pandemic. Various factors which have affected the recruitment and follow-up in pediatric vaccine clinical trials and various strategies used to curtail subject dropout and protocol deviations during COVID-19 pandemic were studied in detail. Results: The primary and most visible impact of the COVID-19 pandemic was that protocol deviations and study dropouts were significantly higher for the trials conducted during COVID-19 pandemic period. The difference between proportion of protocol deviations and study dropouts in the pediatric vaccine clinical trials conducted during pandemic and trials conducted before pandemic was statistically significant (<0.05). The recruitment for ongoing trials was also adversely affected. Conclusion: At our site, the COVID-19 pandemic has affected the conduct and recruitment of pediatric vaccine trials markedly in an adverse manner. The protocol deviations and study dropout were significantly higher during the COVID-19 pandemic period. To counter these effects and still have the trials retain their effectiveness, we found that it is essential to implement measures and strategies for maintaining compliance and safe conduct of clinical trials. Adoption of telemedicine may offer promise in terms of a way forward for conducting clinical trials.

Comparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal delivery