ABSTRACT
Safe, effective, and accessible vaccines are urgently needed to end tuberculosis (TB) by 2030. The 6th Global Forum on TB Vaccines, convened virtually 22–25 February 2022, was hosted by Toulouse, France, under the high patronage of President Emmanuel Macron, and the patronages of Minister for Solidarity and Health, Olivier Véran, and Minister for Higher Education, Research and Innovation, Frédérique Vidal. The theme for the meeting, "New horizons for TB vaccines”, reflected the changing landscape in which TB vaccine research and development (R&D) is being conducted: TB vaccines advancing into late-stage clinical trials and toward licensure, innovative research toward diversifying the TB vaccine pipeline and developing the next generation of candidates, increasing political, civil society, and community support for TB vaccines, and the ongoing COVID-19 pandemic. In this report, we summarize key themes and findings from the meeting, highlighting progress and gaps in the TB vaccine field.
ABSTRACT
Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe disease that affects a small proportion of children exposed to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Differences in SARS-CoV-2 antibody responses and immune gene expression between SARS-CoV-2-infected children who develop MIS-C and those who do not may provide insight into the mechanism of MIS-C. Objectives: To determine the difference in SARS-CoV2 antibody responses and immune gene expression in children with MIS-C and healthy children with evidence of previous SARS-CoV2 infection. Methods: Healthy children presenting for elective surgery and those with MIS-C were recruited between 22 June 2020 and 5 November 2020 from a single paediatric hospital during the first wave of SARSCoV- 2 in the region. Clinical data, whole blood RNA and serum were collected. Titres of SARS-CoV-2 spike-specific antibody (SAb) and their capacity to perform neutralization, antibody-dependent cellular phagocytosis (ADCP) and antibody dependant cellular cytotoxicity (ADCC) were measured. Whole blood RNA gene expression was measured using multiplex Fluidigm quantitative Polymerase Chain Reaction (qPCR) with a panel of 84 immune genes. Principal component analysis was performed to assess for differences in gene expression. A linear regression model was developed with a forward stepwise model selection method to assess which genes associated with Creactive protein (CRP) in MIS-C after controlling for the neutrophil to lymphocyte ratio (NLR). Results: Twenty-three children with MIS-C and 25 healthy children were recruited. Nine healthy children had detectable SARS-CoV-2 serum antibodies (healthy exposed). No children had preceding clinical disease related to SARS-CoV-2 infection. Comparing children with MIS-C and healthy exposed children showed no difference in SAb binding responses (p=0.372) or ADCC (p=0.992). Increased neutralisation titre (p=0.084) and ADCP (p=0.086) in children with MIS-C was observed although was non-significant. Antibody function or titre did not change over time or with treatment in MIS-C. There was a clear distinction in immune gene expression between healthy children and those with MIS-C. Immune gene expression in MIS-C resolved to become indistinct from healthy children with time. Whole blood immune gene expression associated with an abundance of neutrophils in MIS-C. In a model that accounted for 66% of the variance in CRP (adjusted R2 = 0.66) the expression of IL27 accounted for 64% of the model effect (B=35;p<0.001) followed by NLR (15%, B=6.6, p=0.002) and the expression of MCP2 (11%, B=-14.59, p=0.008). Conclusion: Comparing children infected with SARS-COV-2 from the same time period and region with or without MIS-C provides unique mechanistic insight into the disease. A trend towards higher SAb titres and ADCP implies a distinct humoral immune response to SARSCOV- 2 in children with MIS-C, although further studies are required to validate this observation. The resolution of the abnormal immune gene expression in MIS-C implies a monophasic immune perturbation. The association of IL27 and MCP2 with CRP suggests that these may be important targets in future studies for possible pathogenicity and as potential biomarkers in MIS-C.
ABSTRACT
Introduction Respiratory pathogens such as influenza viruses may play an influential role in the pathogenesis of TB by negatively affecting immunity against Mycobacterium tuberculosis (MTB). We discovered and validated a transcriptomic signature of risk (SOR), based on mRNA expression of 11 IFN stimulated genes (ISG), which prospectively differentiates between incident TB cases and healthy controls. The SOR score is computed from expression abundance of multiple ISG transcript pairs in peripheral blood, whereby each pair functions as a ?vote? for or against TB risk. We aimed to identify respiratory pathogens other than MTB that might also associate with this SOR score and test whether the SOR score differentiates between individuals with and without respiratory pathogens. Methods We conducted a nested cross-sectional study of the upper respiratory tract microbiome. Upon consent, participants were consecutively enrolled into the study and provided one nasopharyngeal, one oropharyngeal and a PAXgene blood sample. Host blood SOR scores were computed from Ct values for each of the 11 genes, measured by microfluidic qRT-PCR. We used multiplex real-time PCR to detect 33 pathogens including bacteria, viruses and fungi in the nasopharyngeal and oropharyngeal samples Multivariate linear regression was used to identify pathogens associated with, and estimate their effect on, the SOR score. Wilcoxon rank sum tests and receiver-operating-characteristic (ROC) curves were used to differentiate participants with and without respiratory pathogens. Results 1,000 HIV-negative volunteers aged between 18 and 60 years were enrolled. 13 viral and nine bacterial pathogens were detected. Overall prevalence of respiratory pathogens was 43%: 4% were viruses only, 35.8% bacteria only, and 3.2% were a combination of viruses and bacteria. Influenza C, rhinoviruses, coronavirus OC43, adenoviruses, and mycoplasma pneumoniae were significantly associated (Table 1) with a high SOR score. In ROC curve analysis the SOR score differentiated participants as follows;virus vs no-pathogen (area under the curve;AUC) AUC=0.72, 95% CI: 0.63-0.81, virus vs bacteria AUC=0.72, 95% CI: 0.63-0.81, bacteria vs no-pathogen AUC=0.51, 95% CI: 0.48-0.55 (no difference). Participants with either viruses only or both viruses and bacteria had significantly higher (P=0.001) SOR scores (median 47% and 43%, respectively) compared to participants without pathogens (median 14%) or participants with bacteria only (median 13%). Conclusion Participants with upper respiratory tract viral colonization or infection had elevated SOR scores, suggesting induction of interferon signalling. Infection or colonization with respiratory viruses is likely to result in false positive results for other transcriptomic signatures of tuberculosis based on ISGs (Table Presented) .