Abstract Breakthrough findings in the clinical and preclinical development of tuberculosis (TB) vaccines have galvanized the field and suggest, for the first time since the development of bacille Calmette-Guérin (BCG), that a novel and protective TB vaccine is on the horizon. Here we highlight the TB vaccines that are in the development pipeline and review the basis for optimism in both the clinical and preclinical space. We describe immune signatures that could act as immunological correlates of protection (CoP) to facilitate the development and comparison of vaccines. Finally, we discuss new animal models that are expected to more faithfully model the pathology and complex immune responses observed in human populations. 

Key advances in vaccine development for tuberculosis—success and challenges

<h2>Summary</h2> Adjuvants play pivotal roles in vaccine development, enhancing immunization efficacy through prolonged retention and sustained release of antigen, lymph node targeting, and regulation of dendritic cell activation. Adjuvant-induced activation of innate immunity is achieved via diverse mechanisms: for example, adjuvants can serve as direct ligands for pathogen recognition receptors or as inducers of cell stress and death, leading to the release of immunostimulatory-damage-associated molecular patterns. Adjuvant systems increasingly stimulate multiple innate pathways to induce greater potency. Increased understanding of the principles dictating adjuvant-induced innate immunity will subsequently lead to programming specific types of adaptive immune responses. This tailored optimization is fundamental to next-generation vaccines capable of inducing robust and sustained adaptive immune memory across different cohorts. 

Vaccine adjuvants: Tailoring innate recognition to send the right message.

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.

Vaccine development against tuberculosis before and after Covid-19

ABSTRACT One-quarter of the world’s population is infected with Mycobacterium tuberculosis (Mtb). After initial exposure, more immune-competent persons develop asymptomatic latent tuberculosis infection (LTBI) but not active diseases, creates an extensive reservoir at risk of developing active tuberculosis. Previously, we constructed a novel recombinant Sendai virus (SeV)-vectored vaccine encoding two dominant antigens of Mtb, which elicited immune protection against acute Mtb infection. In this study, nine Mtb latency-associated antigens were screened as potential supplementary vaccine candidate antigens, and three antigens (Rv2029c, Rv2028c, and Rv3126c) were selected based on their immune-therapeutic effect in mice, and their elevated immune responses in LTBI human populations. Then, a recombinant SeV-vectored vaccine, termed SeV986A, that expresses three latency-associated antigens and Ag85A was constructed. In murine models, the doses, titers, and inoculation sites of SeV986A were optimized, and its immunogenicity in BCG-primed and BCG-naive mice were determined. Enhanced immune protection against the Mtb challenge was shown in both acute-infection and latent-infection murine models. The expression levels of several T-cell exhaustion markers were significantly lower in the SeV986A-vaccinated group, suggesting that the expression of latency-associated antigens inhibited the T-cell exhaustion process in LTBI infection. Hence, the multistage quarter-antigenic SeV986A vaccine holds considerable promise as a novel post-exposure prophylaxis vaccine against tuberculosis.

A multistage Sendai virus vaccine incorporating latency-associated antigens induces protection against acute and latent tuberculosis

The absence of validated correlates of protection (CoPs) hampers the rational design and clinical development of new tuberculosis vaccines. In this review, we provide an overview of the potential CoPs in tuberculosis vaccine research. Major hindrances and potential opportunities are then discussed. Based on recent progress, it is reasonable to anticipate that success in the ongoing efforts to identify CoPs would be a game-changer in tuberculosis vaccine development. 

Immune correlates of protection as a game changer in tuberculosis vaccine development

Adjuvant-containing subunit vaccines represent a promising approach for protection against tuberculosis (TB), but current candidates require refrigerated storage. Here we present results from a randomized, double-blinded Phase 1 clinical trial (NCT03722472) evaluating the safety, tolerability, and immunogenicity of a thermostable lyophilized single-vial presentation of the ID93 + GLA-SE vaccine candidate compared to the non-thermostable two-vial vaccine presentation in healthy adults. Participants were monitored for primary, secondary, and exploratory endpoints following intramuscular administration of two vaccine doses 56 days apart. Primary endpoints included local and systemic reactogenicity and adverse events. Secondary endpoints included antigen-specific antibody (IgG) and cellular immune responses (cytokine-producing peripheral blood mononuclear cells and T cells). Both vaccine presentations are safe and well tolerated and elicit robust antigen-specific serum antibody and Th1-type cellular immune responses. Compared to the non-thermostable presentation, the thermostable vaccine formulation generates greater serum antibody responses (p < 0.05) and more antibody-secreting cells (p < 0.05). In this work, we show the thermostable ID93 + GLA-SE vaccine candidate is safe and immunogenic in healthy adults. 

/pdf/safety-and-immunogenicity-of-a-thermostable-id93-gla-se-3ejmquos.pdf

Safety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults

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Safety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults