Development of a TB vaccine trial site in Africa and lessons from the Ebola experience.

The EMA Framework of Collaboration With Academic Stakeholders.

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 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.

<p>The causative agents of Tuberculosis (Tb), Mycobacterium tuberculosis and Mycobacterium bovis, subvert a number of host immune mechanisms to promote persistence of infection in the human host. Infection with these immunoevasive pathogens is estimated to cause 1.8 million deaths per year. The only Tb vaccine currently available is an attenuated form of M. bovis, called bacille Calmette Guerin (BCG), and its efficacy is highly variable. Thus, development of more effective vaccine strategies for Tb is of significant importance. Host-derived natural CD4+CD25+ T regulatory cells (Tregs) suppress host immune responses and prevent autoimmunity. However, Tregs can also interfere with protective immune responses against chronic infections or with the protective efficacy of vaccines. There is speculation that mycobacteria exploit the suppressive activity of Tregs to permit persistence in the host and that Treg activity also diminishes the protective efficacy of the BCG vaccine. Therefore, to explore the role of Tregs in anti-mycobacterial immunity, I first optimised a protocol to inactivate Tregs in vivo in a murine model, through administration of anti-CD25 monoclonal antibody. In addition, I developed a novel plasmid DNA replicon vaccine against Tb to aid with the assessment of the effect of Tregs on Tb vaccines. I hypothesised that inactivating Tregs in vivo prior to mycobacterial infection would enhance acute immune responses that are thought to be protective under current dogma and thereby enhance bacterial clearance. Enhanced immune responses were observed but, contrary to the hypothesis, inactivation of Tregs did not alter bacterial numbers in the lung. I also hypothesised that inactivating Tregs in vivo prior to live BCG or DNA vaccination would enhance primary and secondary immune responses that are thought to be protective against Tb infection and thereby enhance the protective efficacies of the vaccines. Enhanced vaccine-induced immune responses and accelerated secondary immune responses were observed for the BCG vaccine. However, Treg inactivation did not alter the protective efficacy of the BCG vaccine, and preliminary data suggests Treg inactivation may in fact decrease the protective efficacy of one plasmid DNA vaccine tested. In summary, this thesis illustrates that inactivating natural Tregs does not enhance protection from mycobacterial infection. This implies that inactivation of natural Tregs cannot be used in a therapeutic setting to enhance treatment or vaccination approaches for Tb. More importantly, Treg inactivation enhances immune responses that current dogma regard as protective against Tb infection, but does not correspondingly enhance protection. As a result of this disparity, this thesis questions the validity of measures that are commonly used as immune correlates of protection for Tb vaccine design. Ultimately, the development of more accurate immune correlates of protection for Tb will permit targeted design of more effective Tb vaccination strategies.</p>

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.

Community-Acquired Pneumonia Incidence in Adults Aged 18 Years and Older in Goto City, Japan: A Prospective Population-Based Study

Harnessing bioinformatics for the development of a promising multi-epitope vaccine against tuberculosis: The ZL9810L vaccine

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.

Tuberculosis (TB) is a leading cause of global child mortality. Until the turn of the 21st century, Mycobacterium bovis bacille Calmette-Guerin (BCG) was the only vaccine to prevent TB. The pediatric TB vaccine pipeline has advanced in the past decade to include the evaluation of novel whole cell vaccines to replace infant BCG and investigation of subunit and whole cell vaccines to boost TB immunity during adolescence. We describe the history of BCG, current TB vaccine candidates in clinical trials, and the challenges and opportunities for future TB vaccine research in children. Children are a critical target population for TB vaccines, and expansion of the pediatric TB vaccine pipeline is urgently needed to end the TB pandemic.

Much has already been written on this most recent EVD outbreak—evaluating and dissecting the contributions and failings of the various role-players involved, and considering what can be done differently in future. This article will contribute to this important and ongoing debate and will specifically focus on the international, operational, and national legal frameworks in terms of which large-scale health crises like that of Ebola play out. It will be argued that the very culture and architecture of this transnational legal and operational framework for public health emergencies is isolated from the national realities in which it operates and merely offers a hierarchical authority of what legally ought to be done, with little regard to what is actually necessary and possible on the ground. In considering the most recent Ebola outbreak, and juxtaposing it with the Severe Acute Respiratory Syndrome (“SARS”) outbreak of 2003, it will be shown that a more nuanced transnational legal understanding of public health emergencies is indeed needed—a holistic approach that goes beyond biomedical/scientific and legalistic confines in dealing with disease outbreak and control. It is again important to emphasise here, for the sake of clarity, that this article is exclusively focused on the transnational legal and operational framework in which public health emergencies play out. International humanitarian responses, general public health considerations, as well as other national systemic considerations—like those relating to health systems—although important, will not be considered here. A brief interlude on the methodology of this article also deserves a place here. As already indicated above, much literature exists on the Ebola outbreak, and with the attention now shifting to the Zika virus, it is important to further distinguish the contribution of this article. This article utilises a primarily transdisciplinary lens in narrating the rise and fall of two notable epidemics of the modern world. A variety of sources, from different disciplines and bases, are used in presenting an easily accessible text that recounts key themes of both epidemics—highlighting similarities and differences, and raising important questions for the future. As with most narrative research methodologies, reliance is also placed on newspaper articles in constructing an account of how the two epidemics played out, each in its own particular time and space. The disease narrative ultimately presented in this article, therefore simultaneously serve as a chronicle of the two epidemics, while also reflecting why a more nuanced transnational legal understanding of public health emergencies is indeed needed. To facilitate this discussion and analysis, the content of this article is divided into four parts. First, in Part II, the lifecycle of two epidemics will be considered, Ebola, and the 2003 SARS outbreak. Considering these two outbreaks and the international legal responses thereto provides a valuable lens through which the multiple layers of disease outbreaks and control from the past to the present can be observed. In Part III, this paper provides an overview of the international legal and operational framework for public health emergencies, confined to references and examples from the two outbreaks selected for and discussed in Part II. Part IV considers the national legal responses of those countries most affected by the recent Ebola outbreak and the 2003 SARS outbreak. Part V discusses the question of whether to quarantine or not. Part VI discusses lessons to be learned, and why knowledge production beyond disciplinary confines is necessary. And finally, Part VII of this article concludes with a critical analysis of two observed failings of the current international legal and operational framework for public health emergencies. In considering the shortcomings of the current framework it will be argued that a more holistic approach to disease control is required that looks beyond disciplinary confines.

Even though extreme containment and mitigation strategies were implemented by numerous governments around the world to slow down the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the number of critically ill patients and fatalities keeps rising. This crisis has highlighted the socioeconomic disparities of health care systems within and among countries. As new CoVID policies and responses are implemented to lessen the impact of the virus, it is imperative (1) to consider additional mitigation strategies critical for the development of effective countermeasures, (2) to promote long-term policies and strict regulations of the trade of wildlife and live animal markets, and (3) to advocate for necessary funding and investments in global health, specifically for the prevention of and response to natural and manmade pandemics. This document considers some of these challenges.

Inactivated and live attenuated vaccines have improved human life and significantly reduced morbidity and mortality of several human infectious diseases. However, these vaccines have faults, such as reactivity or suboptimal efficacy and expensive and time-consuming development and production. Additionally, despite the enormous efforts to develop vaccines against some infectious diseases, the traditional technologies have not been successful in achieving this. At the same time, the concerns about emerging and re-emerging diseases urge the need to develop technologies that can be rapidly applied to combat the new challenges. Within the last two decades, the research of vaccine technologies has taken several directions to achieve safe, efficient, and economic platforms or technologies for novel vaccines. This review will give a brief overview of the current state of the novel vaccine technologies, new vaccine candidates in clinical trial phases 1–3 (listed by European Medicines Agency (EMA) and Food and Drug Administration (FDA)), and vaccines based on the novel technologies which have already been commercially available (approved by EMA and FDA) with the special reference to pandemic COVID-19 vaccines.Key points• Vaccines of the new generation follow the minimalist strategy.• Some infectious diseases remain a challenge for the vaccine development.• The number of new vaccine candidates in the late phase clinical trials remains low.

BackgroundBoth FDA and EMA reward/demand pediatric oncology studies. Do they advance pediatric cancer care?MethodsWe analysed publications of FDA representatives,1–3 FDA-triggered pediatric oncology studies in the literature and in www.clinicaltrials.gov,4 and...

Background:The authors performed gap analyses on the expedited programs associated with regenerative medicine therapies (RMTs), offered by Food and Drug Administration (FDA), European Medicines Agency (EMA) and Ministry of Food and Drug Safety (MFDS).Methods: The regulations and guidelines on expedited programs (e.g., Regenerative Medicine Advanced Therapy [RMAT] designation) associated with RMTs, and regulatory reviews on approved RMTs were retrieved from the websites of FDA, EMA and MFDS.Based on analyses of the retrieved materials, gap analyses were performed on the qualifying criteria, features and operational frameworks.Included were the comparisons of the expedited programs granted for tisagenlecleucel among the agencies.Results: FDA offers RMAT, Fast Track, Breakthrough Therapy, Priority Review designations, and Accelerated Approval.EMA's programs include PRIority MEdicines (PRIME), Accelerated Assessment, Exceptional Circumstances, and Conditional Marketing Authorisation.MFDS implements a single Fast-Track Processing program.RMAT designation is specific to RMTs and can be utilized with FDA's other expedited programs.PRIME applies to all medicinal products and can be used with EMA's other programs.Fast-Track Processing program is specific to RMTs but combines all expedited features into a single track.Tisagenlecleucel received RMAT, Priority Review and Accelerated Approval for follicular lymphoma from FDA, PRIME for acute lymphocytic leukemia from EMA, and Fast-Track Processing for follicular lymphoma from MFDS.Conclusion: FDA offers the RMAT designation exclusive to expediting the development, review and approval of RMTs in addition to other expedited programs, whereas EMA does RMT approvals under expedited drug approval programs.MFDS implements an exclusive, single-track program for RMTs.

Mycobacterium tuberculosis (M.tb), a bacterial pathogen that causes tuberculosis disease (TB), exerts an extensive burden on global health. The complex nature of M.tb, coupled with different TB disease stages, has made identifying immune correlates of protection challenging and subsequently slowing vaccine candidate progress. In this work, we leveraged two delivery platforms as prophylactic vaccines to assess immunity and subsequent efficacy against low-dose and ultra-low-dose aerosol challenges with M.tb H37Rv in C57BL/6 mice. Our second-generation TB vaccine candidate ID91 was produced as a fusion protein formulated with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion) or as a novel replicating-RNA (repRNA) formulated in a nanostructured lipid carrier. Protein subunit- and RNA-based vaccines preferentially elicit cellular immune responses to different ID91 epitopes. In a single prophylactic immunization screen, both platforms reduced pulmonary bacterial burden compared to the controls. Excitingly, in prime-boost strategies, the groups that received heterologous RNA-prime, protein-boost or combination immunizations demonstrated the greatest reduction in bacterial burden and a unique humoral and cellular immune response profile. These data are the first to report that repRNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing CD4+ and CD8+ T-cell epitopes.