Bacillus Calmette Guérin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent studies supporting a role for antibodies in protection against TB has driven a growing interest in determining their relevance to vaccine development. In this manuscript we review what is known about the humoral immune response to BCG vaccination and re-vaccination across species, including evidence for the induction of specific B cells and antibodies; and how these may relate to protection from TB or bTB. We discuss potential explanations for often conflicting findings and consider how factors such as BCG strain, manufacturing methodology and route of administration influence the humoral response. As novel vaccination strategies include BCG prime-boost regimens, the literature regarding off-target immunomodulatory effects of BCG vaccination on non-specific humoral immunity is also reviewed. Overall, reported outcomes to date are inconsistent, but indicate that humoral responses are heterogeneous and may play different roles in different species, populations, or individual hosts. Further study is warranted to determine whether a new TB vaccine could benefit from the targeting of humoral as well as cell-mediated immunity.

Tuberculosis (TB) continues to pose a serious global health threat, and the current vaccine, BCG, has variable efficacy. However, the development of a more effective vaccine is severely hampered by the lack of an immune correlate of protection. Candidate vaccines are currently evaluated using preclinical animal models, but experiments are long and costly and it is unclear whether the outcomes are predictive of efficacy in humans. Unlike measurements of single immunological parameters, mycobacterial growth inhibition assays (MGIAs) represent an unbiased functional approach which takes into account a range of immune mechanisms and their complex interactions. Such a controlled system offers the potential to evaluate vaccine efficacy and study mediators of protective immunity against Mycobacterium tuberculosis (M.tb). This review discusses the underlying principles and relative merits and limitations of the different published MGIAs, their demonstrated abilities to measure mycobacterial growth inhibition and vaccine efficacy, and what has been learned about the immune mechanisms involved.

Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first 2 years of life, and 129 healthy matched controls, we found the cytomegalovirus-stimulated (CMV-stimulated) IFN-γ response to be associated with CD8 ⁺ T cell activation (Spearman’s rho, P = 6 × 10 ^–8 ). A CMV-specific IFN-γ response was also associated with increased risk of developing TB disease (conditional logistic regression; P = 0.043; OR, 2.2; 95% CI, 1.02–4.83) and shorter time to TB diagnosis (Log Rank Mantel-Cox, P = 0.037). CMV ⁺ infants who developed TB disease had lower expression of NK cell–associated gene signatures and a lower frequency of CD3 ^– CD4 ^– CD8 ^– lymphocytes. We identified transcriptional signatures predictive of TB disease risk among CMV ELISpot–positive (area under the receiver operating characteristic [AUROC], 0.98, accuracy, 92.57%) and –negative (AUROC, 0.9; accuracy, 79.3%) infants; the CMV ^– signature was validated in an independent infant study (AUROC, 0.71; accuracy, 63.9%). A 16-gene signature that previously identified adolescents at risk of developing TB disease did not accurately classify case and control infants in this study. Understanding the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.

Migrants and ethnic minorities in the UK have higher rates of tuberculosis (TB) compared with the general population. Historically, much of the disparity in incidence between UK-born and migrant populations has been attributed to differential pathogen exposure, due to migration from high-incidence regions and the transnational connections maintained with TB endemic countries of birth or ethnic origin. However, focusing solely on exposure fails to address the relatively high rates of progression to active disease observed in some populations of latently infected individuals. A range of factors that disproportionately affect migrants and ethnic minorities, including genetic susceptibility, vitamin D deficiency and co-morbidities such as diabetes mellitus and HIV, also increase vulnerability to infection withMycobacterium tuberculosis (M.tb)or reactivation of latent infection. Furthermore, ethnic socio-economic disparities and the experience of migration itself may contribute to differences in TB incidence, as well as cultural and structural barriers to accessing healthcare. In this review, we discuss both biological and anthropological influences relating to risk of pathogen exposure, vulnerability to infection or development of active disease, and access to treatment for migrant and ethnic minorities in the UK.

The development of a functional biomarker assay in the tuberculosis (TB) field would be widely recognized as a major advance in efforts to develop and to test novel TB vaccine candidates efficiently. We present preliminary studies using mycobacterial growth inhibition assays (MGIAs) to detect Mycobacterium bovis BCG vaccine responses across species, and we extend this work to determine whether a standardized MGIA can be applied in characterizing new TB vaccines. The comparative MGIA studies reviewed here aimed to evaluate robustness, reproducibility, and ability to reflect in vivo responses. In doing so, they have laid the foundation for the development of a MGIA that can be standardized and potentially qualified. A major challenge ahead lies in better understanding the relationships between in vivo protection, in vitro growth inhibition, and the immune mechanisms involved. The final outcome would be a MGIA that could be used with confidence in TB vaccine trials. We summarize data arising from this project, present a strategy to meet the goals of developing a functional assay for TB vaccine testing, and describe some of the challenges encountered in performing and transferring such assays.

This review critically assesses the body of research about Measles-Mumps-and-Rubella (MMR) vaccine attitudes and uptake in the United Kingdom (UK) over the past 10 years. We searched PubMed and Scopus, with terms aimed at capturing relevant literature on attitudes about, and uptake of, the MMR vaccine. Two researchers screened for abstract eligibility and after de-duplication 934 studies were selected. After screening, 40 references were included for full-text review and thematic synthesis by three researchers. We were interested in the methodologies employed and grouped findings by whether studies concerned: (1) Uptake and Demographics; (2) Beliefs and Attitudes; (3) Healthcare Worker Focus; (4) Experimental and Psychometric Intervention; and (5) Mixed Methods. We identified group and individual level determinants for attitudes, operating directly and indirectly, which influence vaccine uptake. We found that access issues, often ignored within the public “anti-vax” debate, remain highly pertinent. Finally, a consistent theme was the effect of misinformation or lack of knowledge and trust in healthcare, often stemming from the Wakefield controversy. Future immunisation campaigns for children, including for COVID-19, should consider both access and attitudinal aspects of vaccination, and incorporate a range of methodologies to assess progress, taking into account socio-economic variables and the needs of disadvantaged groups.