Review of the current TB human infection studies for use in accelerating TB vaccine development: A meeting report

Tools to evaluate and accelerate tuberculosis (TB) vaccine development are needed to advance global TB control strategies. Validated human infection studies for TB have the potential to facilitate breakthroughs in understanding disease pathogenesis, identify correlates of protection, develop diagnostic tools, and accelerate and de-risk vaccine and drug development. However, key challenges remain for realizing the clinical utility of these models, which require further discussion and alignment amongst key stakeholders. In March 2023, the Wellcome Trust and the International AIDS Vaccine Initiative (IAVI) convened international experts involved in developing both TB and Bacillus Calmette-Guerin (BCG) human infection studies (including mucosal and intradermal challenge routes) to discuss the status of each of the models and the key enablers to move the field forward. This report provides a summary of the presentations and discussion from the meeting. Discussions identified key issues, including demonstrating model validity, to provide confidence for vaccine developers, which may be addressed through demonstration of known vaccine effects, e.g. BCG vaccination in specific populations, and by comparing results from field efficacy and human infection studies. The workshop underscored the importance of establishing safe and acceptable studies in high-burden settings, and the need to validate more than one model to allow for different scientific questions to be addressed as well as to provide confidence to vaccine developers and regulators around use of human infection study data in vaccine development and licensure pathways

Practical considerations for a TB controlled human infection model (TB-CHIM); the case for TB-CHIM in Africa, a systematic review of the literature and report of 2 workshop discussions in UK and Malawi

Background: Tuberculosis (TB) remains a major challenge in many domains including diagnosis, pathogenesis, prevention, treatment, drug resistance and long-term protection of the public health by vaccination. A controlled human infection model (CHIM) could potentially facilitate breakthroughs in each of these domains but has so far been considered impossible owing to technical and safety concerns. Methods: A systematic review of mycobacterial human challenge studies was carried out to evaluate progress to date, best possible ways forward and challenges to be overcome. We searched MEDLINE (1946 to current) and CINAHL (1984 to current) databases; and Google Scholar to search citations in selected manuscripts. The final search was conducted 3rd February 2022. Inclusion criteria: adults ≥18 years old; administration of live mycobacteria; and interventional trials or cohort studies with immune and/or microbiological endpoints. Exclusion criteria: animal studies; studies with no primary data; no administration of live mycobacteria; retrospective cohort studies; case-series; and case-reports. Relevant tools (Cochrane Collaboration for RCTs and Newcastle-Ottawa Scale for non-randomised studies) were used to assess risk of bias and present a narrative synthesis of our findings. Results: The search identified 1,388 titles for review; of these 90 were reviewed for inclusion; and 27 were included. Of these, 15 were randomised controlled trials and 12 were prospective cohort studies. We focussed on administration route, challenge agent and dose administered for data extraction. Overall, BCG studies including fluorescent BCG show the most immediate utility, and genetically modified Mycobacteria tuberculosis is the most tantalising prospect of discovery breakthrough. Conclusions: The TB-CHIM development group met in 2019 and 2022 to consider the results of the systematic review, to hear presentations from many of the senior authors whose work had been reviewed and to consider best ways forward. This paper reports both the systematic review and the deliberations

Details of 43 validated type I genic-SSR markers tested for polymorphism among 8 mango varieties.

<p>Details of 43 validated type I genic-SSR markers tested for polymorphism among 8 mango varieties.</p

NGS sequence and assembly statistics of mango leaf transcriptome varieties Neelam, Dashehari and their hybrid Amrapali.

<p>NGS sequence and assembly statistics of mango leaf transcriptome varieties Neelam, Dashehari and their hybrid Amrapali.</p

Categorization of 22,306 SNPs into eight classes on the basis of heterozygosity in the hybrid Amrapali <i>vis a vis</i> its parental varieties Neelam and Dashehari.

<p>Categorization of 22,306 SNPs into eight classes on the basis of heterozygosity in the hybrid Amrapali <i>vis a vis</i> its parental varieties Neelam and Dashehari.</p

Summary of 12,539 unigenes of <i>M</i>. <i>Indica</i> classified into 58 Transcription Factor (TF) category.

<p>Among them bHLH, NAC, MYB, WRKY proteins were the most abundant.</p

Wet lab validation of <i>in silico</i> designed genic-SSR markers of mango.

<p><b>a)</b> PCR results with 48 different SSR markers (MSSR1- MSSR 48) in mango variety Amrapali; <b>b)</b> Allelic polymorphism of MSSR-13 in 8 different varieties of Mango 1. Neelam, 2. Dashehari, 3. Amrapali, 4. Chausa, 5. Pusa Lalima, 6. Ratual, 7. Mallika and 8. Alphonso.</p

Leaf Transcriptome Sequencing for Identifying Genic-SSR Markers and SNP Heterozygosity in Crossbred Mango Variety ‘Amrapali’ (<i>Mangifera indica</i> L.)

<div><p>Mango (<i>Mangifera indica</i> L.) is called “king of fruits” due to its sweetness, richness of taste, diversity, large production volume and a variety of end usage. Despite its huge economic importance genomic resources in mango are scarce and genetics of useful horticultural traits are poorly understood. Here we generated deep coverage leaf RNA sequence data for mango parental varieties ‘Neelam’, ‘Dashehari’ and their hybrid ‘Amrapali’ using next generation sequencing technologies. De-novo sequence assembly generated 27,528, 20,771 and 35,182 transcripts for the three genotypes, respectively. The transcripts were further assembled into a non-redundant set of 70,057 unigenes that were used for SSR and SNP identification and annotation. Total 5,465 SSR loci were identified in 4,912 unigenes with 288 type I SSR (n ≥ 20 bp). One hundred type I SSR markers were randomly selected of which 43 yielded PCR amplicons of expected size in the first round of validation and were designated as validated genic-SSR markers. Further, 22,306 SNPs were identified by aligning high quality sequence reads of the three mango varieties to the reference unigene set, revealing significantly enhanced SNP heterozygosity in the hybrid Amrapali. The present study on leaf RNA sequencing of mango varieties and their hybrid provides useful genomic resource for genetic improvement of mango.</p></div

COG functional classification.

<p>A total of 9,847 unigenes were assigned to 24 COG categories.</p