Identification of subclinical tuberculosis in household contacts using exposure scores and contact investigations.

BACKGROUND: The goal of tuberculosis elimination put forward in the End TB Strategy prioritizes diagnosis and treatment of incipient and subclinical TB, recently defined by key stakeholders as "asymptomatic, early pre-clinical disease during which pathology evolves". Regarded as indicative of a high risk of TB progression, considerable efforts have been made to identify these cases through exploration of biomarkers. The present study aimed to evaluate simple scoring systems for TB exposure as screening tools for subclinical TB, the only identifiable of the incipient and subclinical disease states, in a contact investigation (CI) setting of low HIV-prevalence. METHODS: Nested within a large prospective study in household contacts (HHCs) of smear positive pulmonary TB cases in South-India conducted 2010-2012, we assessed 1) the association between the Tuberculosis Contact Score (TCS) and the Infectivity Score, with established tools for Mycobacterium tuberculosis (Mtb) infection, corrected for established TB risk factors, and 2) the capability of the TB exposure scores to identify subclinical TB defined by Mtb-culture positivity in sputum or gastric aspirate (subjects < 5 years) specimen. RESULTS: Of 525 HHCs, 29 were Mtb-culture positive and 96.6% of these asymptomatic. The TCS and the Infectivity Score associated with positive Tuberculin Skin Test and QuantiFeron TB-Gold In-tube assay (QFT) results in multivariate analyses (TCS: ORTST 1.16, 95% CI: 1.01, 1.33; ORQFT 1.33 95% CI: 1.16, 1.51. Infectivity Score: ORTST 1.39, 95% CI: 1.10, 1.76; ORQFT 1.41 95% CI: 1.16, 1.71). The Infectivity Score showed a moderate capability to identify subclinical TB (AUC of 0.61, 95% CI: 0.52, 0.70). CONCLUSIONS: Although our results did not identify an easily applicable screening tool for subclinical TB, the present study indicates that focusing on TB-related symptoms in CI settings may be of limited value for early identification of HHCs with high risk for TB progression.

Precision Medicine and Vaccination of Older Adults: From Reactive to Proactive (A Mini-Review).

As populations age globally, the health of older adults is looming larger on the agendas of public health bodies. In particular, the priority is to ensure that older adults remain healthy, independent, and engaged in their communities. In other words, ensuring that increasing life spans are matched by increasing "health spans," meaning years spent in good health. Chronic conditions such as cancer or respiratory and cardiovascular diseases account for the bulk of the disease burden in older adults, and the consensus is that these can best be tackled by effective primary prevention. However, given the diverse nature of older populations, whose prior health experiences can be complicated by multi-morbidity and poly-pharmacy, effective primary prevention can be challenging. One approach that is gaining momentum is what is called "precision" or P4 medicine. The acronym stands for "predictive, personalized, preventive, participatory" medicine, and is based on the premise that preventing disease is better than treating it. However, effective prevention requires the ability to predict disease risk for a given patient, the tailoring of treatment to their circumstances, and their consent for or participation in the offered treatment. A P4 approach may seem counter-intuitive, given that vaccination is generally considered a public health intervention. However, in this article, we discuss the application of P4 medicine as a complement to planning the vaccination of older individuals, with a special focus on the important role that vaccine-preventable infections play in the burden of non-communicable disease.

Incidence of tuberculosis among school-going adolescents in South India.

BACKGROUND: Tuberculosis (TB) incidence data in vaccine target populations, particularly adolescents, are important for designing and powering vaccine clinical trials. Little is known about the incidence of tuberculosis among adolescents in India. The objective of current study is to estimate the incidence of pulmonary tuberculosis (PTB) disease among adolescents attending school in South India using two different surveillance methods (active and passive) and to compare the incidence between the two groups. METHODS: The study was a prospective cohort study with a 2-year follow-up period. The study was conducted in Palamaner, Chittoor District of Andhra Pradesh, South India from February 2007 to July 2010. A random sampling procedure was used to select a subset of schools to enable approximately 8000 subjects to be available for randomization in the study. A stratified randomization procedure was used to assign the selected schools to either active or passive surveillance. Participants who met the criteria for being exposed to TB were referred to the diagnostic ward for pulmonary tuberculosis confirmation. A total number of 3441 males and 3202 females between the ages 11 and less than 18 years were enrolled into the study. RESULTS: Of the 3102 participants in the active surveillance group, four subjects were diagnosed with definite tuberculosis, four subjects with probable tuberculosis, and 71 subjects had non-tuberculous Mycobacteria (NTM) isolated from their sputum. Of the 3541 participants in the passive surveillance group, four subjects were diagnosed with definite tuberculosis, two subjects with probable tuberculosis, and 48 subjects had non-tuberculosis Mycobacteria isolated from their sputum. The incidence of definite + probable TB was 147.60 / 100,000 person years in the active surveillance group and 87 / 100,000 person years in the passive surveillance group. CONCLUSION: The incidence of pulmonary tuberculosis among adolescents in our study is lower than similar studies conducted in South Africa and Eastern Uganda - countries with a higher incidence of tuberculosis and human immunodeficiency virus (HIV) than India. The study data will inform sample design for vaccine efficacy trials among adolescents in India.

Biomarkers for risk of developing active tuberculosis in contacts of TB patients: a prospective cohort study.

Identifying those Mycobacterium tuberculosis latent-infected individuals most at risk of developing active tuberculosis (TB) using routine clinical and laboratory tests remains a huge challenge in TB control efforts. We conducted a prospective longitudinal study of clinical and laboratory markers associated with the risk of developing active TB in contacts with latent M. tuberculosis infection.HIV-negative household contacts (n=296) of pulmonary TB patients underwent monitoring of clinical features, full blood cell counts, tuberculin skin text (TST) and chest radiography performed regularly during 18 months of follow-up. Paired statistical tests, a Kaplan-Meier analysis and Cox proportional hazard modelling were performed on variables between contacts progressing or not progressing to active TB.The appearance of TB disease symptoms in contacts was significantly associated with an elevated peripheral percentage of blood monocytes (adjusted hazard ratio (aHR) 6.25, 95% CI 1.63-23.95; p<0.01), a ≥14 mm TST response (aHR 5.72, 95% CI 1.22-26.80; p=0.03) and an increased monocyte:lymphocyte ratio (aHR 4.97, 95% CI 1.3-18.99; p=0.03). Among contacts having TST ≥14 mm, a strong association with risk of progression to TB was found with an elevated blood monocyte percentage (aHR 8.46, 95% CI 1.74-41.22; p<0.01).Elevated percentage of peripheral blood monocytes plus an elevated TST response are potential biomarkers for identifying contacts of TB patients at highest risk of developing active TB.

Nonstructural barriers to adult vaccination.

Adult vaccination coverage remains low, despite vaccine recommendations, improved access, and reimbursement. Low vaccination coverage and an aging population at higher risk from vaccine-preventable diseases lead to preventable disability and deaths, straining healthcare systems. An Advisory Board meeting was, therefore, held to identify non-structural barriers to adult vaccination and discuss potential solutions to increase uptake. Many non-structural factors can influence vaccine uptake, such as heterogeneity in the population, (fear of) vaccine shortages, incentives, or mandates for vaccination, understanding of disease burden and personal risks, time and opportunity for healthcare providers (HCPs) to discuss and deliver vaccines during general practice or hospital visits, trust in the health system, and education. To address these barriers, push-pull mechanisms are required: to pull patients in for vaccination and to push HCP performance on vaccination delivery. For patients, the focus should be on lifelong prevention and quality of life benefits: personal conversations are needed to increase confidence and knowledge about vaccination, and credible communication is required to build trust in health services and normalize vaccination. For providers, quality measurements are required to prioritize vaccination and ensure opportunities to check vaccination status, discuss and deliver vaccines are not missed. Financial and quality-based incentives may help increase uptake.

What is the context?● As populations age, healthcare systems are increasingly struggling with the burden of adult disease. Multiple vaccines are already recommended for adults throughout their lifetime, and more are coming soon, however, even in countries with subsidized programs, few adults are fully vaccinated, leading to frequent cases of illness, disability, hospitalization, or death, which could have been prevented.What is new?● Experts from Europe and the US joined an Advisory Board meeting to find out what is stopping people from getting vaccinated, particularly when vaccines are free, and how this can be helped in future.● The decision to get vaccinated can vary for different subgroups of the population, and can be influenced by vaccine shortages, rules about vaccination, and understanding the disease severity and need for vaccination. In addition, doctors may not have enough time and opportunity to discuss and provide vaccines during visits or may not feel comfortable raising the issue of vaccination with their patients.● To overcome these issues, both patients and doctors must change. Patients need: greater awareness of how illness impacts overall health and quality of life; better conversations with their doctors to address vaccination concerns; and trustworthy information from health services. For providers, vaccination prioritization should be linked to quality measurements, with collaboration from trusted community members to reinforce the importance of prevention, thus ensuring opportunities are not missed to discuss prevention and vaccinate. Normalizing adult vaccination is important for this.What is the impact?● Taking a patient centered prevention approach will help protect adults and ease the burden of vaccine-preventable disease.

Sustaining the momentum for adult vaccination post-COVID-19 to leverage the global uptake of life-course immunisation: A scoping review and call to action.

OBJECTIVES: The COVID-19 pandemic changed the adult vaccination landscape, possibly permanently. This review attempts to quantitate the magnitude of those changes. METHODS: PubMed was searched for studies on adult / life-course vaccination between 1 January 2020 until 8 November 2022. RESULTS: Twenty-one articles were identified and observations summarised as positive developments/impediments to life-course immunisation, and areas needing policy and structural reform. Unprecedented funding, international co-operation and technical advances led to COVID-19 vaccines authorised in record time. Investments in infrastructure and an expanded healthcare workforce streamlined vaccine delivery to adults. Constant media coverage and targeted messaging have improved health literacy. Conversely, the speed of vaccine development was perceived as a safety risk, and an 'infodemic' of misinformation propagated through social media negatively influenced vaccine uptake. Vaccine access and affordability remains inequitable among older adults and minority groups. CONCLUSIONS: The COVID pandemic led to an opportunity to permanently change policies, attitudes, and systems for vaccine delivery to adults to establish a global life-course approach to immunisation. This is a call for action to sustain the momentum triggered by the COVID-19 pandemic. Addressing inequalities, improving health literacy and optimally using social media are critical to sustain adult vaccinations in post-COVID-19 era.

Maintaining a 'fit' immune system: the role of vaccines.

INTRODUCTION: Conventionally, vaccines are thought to induce a specific immune response directed against a target pathogen. Long recognized but poorly understood nonspecific benefits of vaccination, such as reduced susceptibility to unrelated diseases or cancer, are now being investigated and may be due in part to "trained immunity'. AREAS COVERED: We discuss 'trained immunity' and whether vaccine-induced 'trained immunity' could be leveraged to prevent morbidity due to a broader range of causes. EXPERT OPINION: The prevention of infection i.e. maintaining homeostasis by preventing the primary infection and resulting secondary illnesses, is the pivotal strategy used to direct vaccine design and may have long-term, positive impacts on health at all ages. In the future, we anticipate that vaccine design will change to not only prevent the target infection (or related infections) but to generate positive modifications to the immune response that could prevent a wider range of infections and potentially reduce the impact of immunological changes associated with aging. Despite changing demographics, adult vaccination has not always been prioritized. However, the SARS-CoV-2 pandemic has demonstrated that adult vaccination can flourish given the right circumstances, demonstrating that harnessing the potential benefits of life-course vaccination is achievable for all.

Healthy ageing: Herpes zoster infection and the role of zoster vaccination.

Populations are ageing worldwide, with considerable time lived in ill-health, putting upwards pressure on healthcare budgets. Healthy ageing is defined as maintaining functional ability, including the ability to: meet basic needs; learn, grow and make decisions; be mobile; build and maintain relationships; and contribute to society. The risk and impact of infectious diseases increase with age due to immunosenescence. Vaccination can help to prevent disease in older adults, promoting healthy ageing and active lives. Herpes zoster (HZ) occurs when the varicella zoster virus is reactivated due to declining immunity. HZ is common, with a lifetime risk of one-third, and increases in incidence with age. HZ is associated with severe and intense pain, substantially affecting the functional status of patients as well as their overall health-related quality of life. HZ and its complications may result in prolonged morbidity, including persistent pain (post-herpetic neuralgia, PHN), hearing impairment, vision loss and increased risk of stroke and myocardial infarction. HZ and PHN are difficult to treat, substantiating the benefits of prevention. Vaccines to prevent HZ include a recombinant zoster vaccine (RZV). RZV has shown efficacy against the HZ burden of disease and HZ burden of interference on activities of daily living of over 90% in immunocompetent adults aged ≥50 years. Vaccine efficacy against HZ was maintained at over 70% at 10 years post-vaccination. Adult vaccination, including against HZ, has the potential to reduce burden of disease, thus helping to maintain functioning and quality of life to support healthy ageing in older adults.

Review of the unmet medical need for vaccination in adults with immunocompromising conditions: An Indian perspective.

Immunocompromised (IC) populations are at increased risk of vaccine-preventable diseases (VPDs). In India, the concern of VPDs in IC populations is particularly acute due to the prevalence of crowded living situations, poor sanitation and variable access to healthcare services. We present a narrative review of IC-related disease and economic burden, risk of VPDs and vaccination guidelines, based on global and India-specific literature (2000-2022). IC conditions considered were cancer, diabetes mellitus, chronic kidney disease, respiratory disorders, disorders treated with immunosuppressive therapy, and human immune deficiency virus (HIV). The burden of IC populations in India is comparable to the global population, except for cancer and HIV, which have lower prevalence compared with the global average. Regional and socioeconomic inequalities exist in IC prevalence; VPDs add to the burden of IC conditions, especially in lower income strata. Adult vaccination programs could improve health and reduce the economic impact of VPDs in IC populations.

What is the context?The population is aging, both globally and in India. Older age is associated with a weakened immune system. People with an immunocompromised (IC) status have a higher risk of contracting infections. The combination of these conditions greatly increases risk from infectious disease. A large percentage of infections, referred to as vaccine-preventable diseases (VPDs), could be avoided by vaccination. However, India-specific guidelines for adult immunization are limited and there is a low awareness of these recommendations among healthcare professionals and patients. What is new? The proportion of people with IC conditions in India is comparable to that seen in other countries. However, the risk of VPDs, such as influenza and bacterial pneumonia, is of particular concern in India; several factors, such as crowded living situation, poor hygienic conditions, and lack of access to healthcare may favor the spread of infections. The consequences of infections have the greatest impact on families with low income. Furthermore, only few India-specific guidelines exist with recommendations for adult immunization. What is the impact? There is a need to protect the growing IC populations against VPDs. The introduction of public healthcare and the experience from the nationwide COVID−19 immunization program in India provide an opportunity to extend adult vaccination programs covering other VPDs. Immunization programs could reduce the economic and disease burden associated with VPDs. Clear national guidelines and communication strategies are required to increase awareness of the benefit of vaccination.

Potential of novel Mycobacterium tuberculosis infection phase-dependent antigens in the diagnosis of TB disease in a high burden setting.

BACKGROUND: Confirming tuberculosis (TB) disease in suspects in resource limited settings is challenging and calls for the development of more suitable diagnostic tools. Different Mycobacterium tuberculosis (M.tb) infection phase-dependent antigens may be differentially recognized in infected and diseased individuals and therefore useful as diagnostic tools for differentiating between M.tb infection states. In this study, we assessed the diagnostic potential of 118 different M.tb infection phase-dependent antigens in TB patients and household contacts (HHCs) in a high-burden setting. METHODS: Antigens were evaluated using the 7-day whole blood culture technique in 23 pulmonary TB patients and in 19 to 21 HHCs (total n = 101), who were recruited from a high-TB incidence community in Cape Town, South Africa. Interferon-gamma (IFN-γ) levels in culture supernatants were determined by ELISA. RESULTS: Eight classical TB vaccine candidate antigens, 51 DosR regulon encoded antigens, 23 TB reactivation antigens, 5 TB resuscitation promoting factors (rpfs), 6 starvation and 24 other stress response-associated TB antigens were evaluated in the study. The most promising antigens for ascertaining active TB were the rpfs (Rv0867c, Rv2389c, Rv2450c, Rv1009 and Rv1884c), with Areas under the receiver operating characteristics curves (AUCs) between 0.72 and 0.80. A combination of M.tb specific ESAT-6/CFP-10 fusion protein, Rv2624c and Rv0867c accurately predicted 73% of the TB patients and 80% of the non-TB cases after cross validation. CONCLUSIONS: IFN-γ responses to TB rpfs show promise as TB diagnostic candidates and should be evaluated further for discrimination between M.tb infection states.

Lifting non-pharmaceutical interventions following the COVID-19 pandemic - the quiet before the storm?

INTRODUCTION: In the first months of the novel coronavirus (COVID-19) pandemic that begun in 2020, non-pharmaceutical interventions (NPIs) have been adopted worldwide. However, the effects of NPI implementation go beyond slowing the spread of COVID-19. Here, we review the non-intended effects that may have arisen from prolonged application of NPIs. AREAS COVERED: NPIs also affected the epidemiology of other infectious diseases, with unprecedentedly low circulation of several respiratory and gastrointestinal viruses being observed worldwide in 2020. While this was a welcome effect for already strained health-care systems, prolonged low exposure to pathogens may result in an increased pool of individuals susceptible to certain diseases. Out-of-season or unusually intense outbreaks of non-vaccine preventable diseases have already been documented as NPIs were gradually eased. In the context of widespread and important disruptions in national vaccination programs during the early phase of the pandemic, the risk of vaccine-preventable disease resurgence after NPIs are lifted cannot be excluded either. EXPERT OPINION: Awareness must be raised of the risk of vaccine-preventable disease resurgence, and efforts need to be made to mitigate this risk, where possible, by increasing vaccination coverage. Research and regulatory opportunities brought on by the COVID-19 pandemic should be seized.

In the first months of the COVID-19 pandemic, the only methods available to slow the spread of the disease were non-pharmaceutical interventions, such as lockdowns, mask wearing, social distancing, school closures, and travel bans. Even after vaccines against COVID-19 became available, combinations of non-pharmaceutical interventions continued to be implemented by most countries, to various extents. Although these measures lowered the number of people who got sick before vaccines and therapies against COVID-19 were available, they also had other consequences for public health. The non-pharmaceutical interventions implemented worldwide have slowed or even stopped the spread of several infectious diseases: since 2020, fewer cases of flu, bronchiolitis, gastroenteritis, and other diseases were recorded compared to pre-pandemic times. This relatively long 2-year period during which people, especially children, were exposed to fewer infections might mean that their immune systems are less prepared to fight these diseases. In addition, vaccination against diseases other than COVID-19 dropped in the early months of the pandemic, meaning that the number of children and adults who are not protected against vaccine-preventable disease has potentially increased. Easing of COVID-19 restrictions has caused a comeback of some diseases against which no vaccine is available, sometimes with more cases than during the pre-pandemic years; there is a risk that this might happen with vaccine-preventable diseases as well. To prevent outbreaks, routine and catch-up vaccinations against other diseases besides COVID-19 should be encouraged and promoted.

Unveiling the contributions of immunization for progressing towards Universal Health Coverage.

The aim of the United Nations' Sustainable Development Goal (SDG)3 is to ensure healthy lives and promote well-being for all, at all ages; including reducing maternal and child mortality, combating communicable and non-communicable diseases, and achieving Universal Health Coverage (UHC). UHC aims to provide everyone with equal access to quality essential and comprehensive healthcare services including preventions, interventions, and treatments, without exposing them to financial hardship. Making progress toward UHC requires significant investment in technical and financial resources and countries are pursuing the implementation of cost-saving measures within health systems to help them achieve UHC. Whilst many countries are far from attaining UHC, all countries, particularly low- and middle-income countries, can take steps toward achieving UHC. This paper discusses key data showing how immunization is a fundamental, cost-effective tool for reducing morbidity and mortality associated with infectious disease in all populations, creating more productive communities, reducing treatment costs, and consequently, facilitating social and economic advancement. Immunization is key to advancing toward UHC by relieving the burden that diseases place on the healthcare services, freeing essential resources to use elsewhere within the healthcare system. Immunization is an essential, readily available strategy that countries can deploy to achieve UHC and the SDG3 agenda.

Capturing the value of vaccination within health technology assessment and health economics: Literature review and novel conceptual framework.

BACKGROUND: Vaccination provides significant health gains to individuals and society and can potentially improve health equity, healthcare systems and national economies. Policy decisions, however, are rarely informed by comprehensive economic evaluations (EE) including vaccination's wide-ranging value. The objective of this analysis was to focus on health technology assessment systems to identify relevant value concepts in order to improve current EE of non-pandemic vaccines. METHODS: Following a literature review, a novel Value of Vaccination (VoV) framework was developed with experts in vaccine EE from developed countries with established health technology assessment systems. RESULTS: Forty-four studies presenting value frameworks or concepts applicable to vaccination were included. Eighteen unique value concepts relevant to EE were identified and defined. These were categorised within the VoV framework using three dimensions, moving from a narrow payer perspective to a more expansive and societal perspective. The dimensions were: (I) conventional payer perspective concepts (e.g., health gains in vaccinees, direct medical costs); (II) conventional societal perspective concepts (e.g., indirect health/economic gains to caregivers/households, productivity in vaccinees); and (III) novel societal concepts (e.g., financial risk protection, peace of mind, societal health gains, healthcare systems security, political stability, social equity and macroeconomic gains). While good quality evidence and methods are available to support concepts in Dimensions I and II, further work is needed to generate the required evidence for vaccination impact on Dimension III concepts. CONCLUSIONS: The devastating effect on nations of the COVID-19 pandemic has helped to highlight the potential far-reaching benefits that many vaccination programmes can offer. This VoV framework is particularly relevant to policy decisions considering EE, and the potential future expansion of non-pandemic vaccination value considerations. The framework helps to understand and compare current value considerations across countries and payer versus societal perspectives. It provides decision-makers with a transparent and logical path to broaden consideration of VoV in EE.

Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice.

Human infection with Mycobacterium tuberculosis can progress to active disease, be contained as latent infection, or be eradicated by the host response. Tuberculosis diagnostics classify a patient into one of these categories. These are not fixed distinct states, but rather are continua along which patients can move, and are affected by HIV infection, immunosuppressive therapies, antituberculosis treatments, and other poorly understood factors. Tuberculosis biomarkers-host or pathogen-specific-provide prognostic information, either for individual patients or study cohorts, about these outcomes. Tuberculosis case detection remains difficult, partly because of inaccurate diagnostic methods. Investments have yielded some progress in development of new diagnostics, although the existing pipeline is limited for tests for sputum-smear-negative cases, childhood tuberculosis, and accurate prediction of reactivation of latent tuberculosis. Despite new, sensitive, automated molecular platforms for detection of tuberculosis and drug resistance, a simple, inexpensive point-of-care test is still not available. The effect of any new tests will depend on the method and extent of their introduction, the strength of the laboratories, and the degree to which access to appropriate therapy follows access to diagnosis. Translation of scientific progress in biomarkers and diagnostics into clinical and public health programmes is possible-with political commitment, increased funding, and engagement of all stakeholders.

Expression of apoptosis-related genes in an Ethiopian cohort study correlates with tuberculosis clinical status.

Mycobacterium tuberculosis remains one of the world's deadliest pathogens in part because of its ability to persist in the face of an active immune response. It has been suggested that apoptosis of infected macrophages is one way in which the host deals with intracellular pathogens and that M. tuberculosis can inhibit this process. To assess the relevance of this process for human disease, we compared the expression of multiple genes involved in the activation of the extrinsic ("death receptor initiated") pathway of apoptosis in 29 tuberculosis patients, 70 tuberculosis contacts and 27 community controls from Ethiopia. We found that there is a strong upregulation of genes for factors that promote apoptosis in PBMC from individuals with active disease, including TNF-alpha and its receptors, Fas and FasL and pro-Caspase 8. The anti-apoptotic factor FLIP, however, was also upregulated. A possible explanation for this dichotomy was given by fractionation of PBMC using CD14, which suggests that macrophage/monocytes may regulate several key molecules differently from non-monocytic cells (especially TNF-alpha and its receptors, a finding confirmed by protein ELISA) potentially reducing the sensitivity to apoptotic death of monocyte/macrophages--the primary host cell for M. tuberculosis. This may represent an important survival strategy for the pathogen.

Modulation of cell death by M. tuberculosis as a strategy for pathogen survival.

It has been clearly demonstrated that in vitro, virulent M. tuberculosis can favor necrosis over apoptosis in infected macrophages, and this has been suggested as a mechanism for evading the host immune response. We recently reported that an effect consistent with this hypothesis could be observed in cells from the blood of TB patients, and in this paper, we review what is known about evasion strategies employed by M. tuberculosis and in particular consider the possible interaction of the apoptosis-inhibiting effects of M. tuberculosis infection with another factor (IL-4) whose expression is thought to play a role in the failure to control M. tuberculosis infection. It has been noted that IL-4 may exacerbate TNF-α-induced pathology, though the mechanism remains unexplained. Since pathology in TB typically involves inflammatory aggregates around infected cells, where TNF-α plays an important role, we predicted that IL-4 would inhibit the ability of cells to remove M. tuberculosis by apoptosis of infected cells, through the extrinsic pathway, which is activated by TNF-α. Infection of human monocytic cells with mycobacteria in vitro, in the presence of IL-4, appears to promote necrosis over apoptosis in infected cells-a finding consistent with its suggested role as a factor in pathology during M. tuberculosis infection.

Heparin-binding, hemagglutinin-specific IFN-gamma synthesis at the site of infection during active tuberculosis in humans.

RATIONALE: Tuberculosis (TB) remains a major cause of mortality. A better understanding of the immune responses to mycobacterial antigens may be helpful to develop improved vaccines and diagnostics. OBJECTIVES: The mycobacterial antigen heparin-binding hemagglutinin (HBHA) induces strong IFN-γ responses by circulating lymphocytes from subjects latently infected with Mycobacterium tuberculosis, and low responses associated with CD4(+) regulatory T (Treg) cells in patients with TB. Here, we investigated HBHA-specific IFN-γ responses at the site of the TB disease. METHODS: Bronchoalveolar lavages, pleural fluids, and blood were prospectively collected from 61 patients with a possible diagnosis of pulmonary or pleural TB. HBHA-specific IFN-γ production was analyzed by flow cytometry and ELISA. The suppressive effect of pleural Treg cells was investigated by depletion experiments. MEASUREMENTS AND MAIN RESULTS: The percentages of HBHA-induced IFN-γ(+) alveolar and pleural lymphocytes were higher for pulmonary (P < 0.0001) and for pleural (P < 0.01) TB than for non-TB controls. Local CD4(+) and CD8(+) T cells produced the HBHA-specific IFN-γ. This local secretion was not suppressed by Treg lymphocytes, contrasting with previously reported data on circulating lymphocytes. CONCLUSIONS: Patients with TB display differential effector and regulatory T-cell responses to HBHA in local and circulating lymphocytes with a predominant effector CD4(+) and CD8(+) response locally, compared with a predominant Treg response among circulating lymphocytes. These findings may be helpful for the design of new vaccines against TB, and the detection of HBHA-specific T cells at the site of the infection may be a promising tool for the rapid diagnosis of active TB.

High heritability of antimycobacterial immunity in an area of hyperendemicity for tuberculosis disease.

Human antimycobacterial immunity is a critical component of tuberculosis (TB) pathogenesis that is often used to infer the presence of TB infection. We report high heritability (>50%) for in vitro secretion of tumor necrosis factor alpha and interferon gamma (IFN-gamma), and the frequency of antigen-specific IFN-gamma(+)CD4(+) and IFN-gamma(+)CD8(+) cells in the response of whole blood to mycobacterial challenge. In principal component analysis, the first 3 components explain 78% of the overall variance consistent with the effect of pleiotropic regulatory genes of human antimycobacterial immunity. These results directly demonstrate the pivotal role played by host genetics in quantitative measures of antimycobacterial immunity underlying immune diagnosis of TB infection.

First in humans: a new molecularly defined vaccine shows excellent safety and strong induction of long-lived Mycobacterium tuberculosis-specific Th1-cell like responses.

Tuberculosis (TB) remains a major killer worldwide. The only available TB-vaccine, the nearly century-old Mycobacterium bovis BCG, has had only a limited effect on TB incidence. Therefore, developing new TB vaccines is a key priority, and the first new generation TB vaccines are now being tested in clinical trials. Here we describe the development and first testing in humans of a novel, wholly synthetic TB subunit vaccine. This vaccine has proven safe and highly immunogenic in all species in which it was tested, including mice, guinea pigs, non-human primates and humans. Most encouragingly, following vaccination in humans, strong IFN-γ responses persisted through at least 2½ years of follow-up, indicating induction of a substantial memory response by this new TB vaccine. These findings encourage further preclinical and clinical studies with TB subunit vaccines and cellular immunity-stimulating new adjuvants.

Effect of vaccination on the use of antimicrobial agents: a systematic literature review.

BACKGROUND: Antimicrobial resistance is a growing global health threat. To preserve the effectiveness of antimicrobials, it is important to reduce demand for antimicrobials. OBJECTIVES: The objective of the study was to screen the existing peer-reviewed literature to identify articles that addressed the potential impact of influenza or Pneumococcus vaccination on antibiotic usage. Data sources: PubMed, Embase Study eligibility criteria: Clinical studies where antimicrobial prescribing was assessed in both vaccinated and unvaccinated populations. Participants and interventions: All patient populations were included (infants, children, adults and elderly), where the effects of the intervention (vaccination) was assessed. RESULTS: We identified unique 3638 publications, of which 26 were judged to be of sufficiently high quality to allow the calculation of the potential impact of vaccination. Of these studies 23/26 found a significant reduction in antibiotic use by at least one of the parameters assessed. LIMITATIONS: Different measures used to define anti-microbial use, studies typically focus on specific risk groups and most studies are from high-income countries. Conclusions and implications of key findings: Despite the limitations of the review, the evidence indicates that improved coverage with existing vaccines may significantly reduce antimicrobial demand. This suggests it may be a valuable tool for antimicrobial stewardship. Key messages While vaccines against a number of pathogens have been studied for their ability to reduce antimicrobial use, currently only vaccination against influenza or pneumococcus has generated sufficient data for analysis Vaccination against either influenza or pneumococcus significantly reduced overall antimicrobial prescribing rates, both in vaccinated individuals and at a population level Maintaining and expanding vaccination coverage thus appears to be a key tool for antimicrobial stewardship.