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ABSTRACTImmunocompromised (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.

Supplemental Digital Content is available in the text.We have explored the added value of interferon-γ (IFNγ)–inducible protein 10 as a read-out of Mycobacterium tuberculosis–specific immunity in young Indian children, where the sensitivity of the IFNγ release assays for tuberculosis is poor. Reduced frequency of indeterminate results and an increased sensitivity for tuberculosis suggest a potential for fewer missed cases with a combined IFNγ/inducible protein 10 read-out in a 4th generation IFNγ release assays.

Tuberculosis (TB) remains a major killer worldwide. The only available TB-vaccine, the nearly century-old Mycobacterium bovisBCG, 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.

ABSTRACTThe majority of healthy individuals exposed to Mycobacterium tuberculosiswill not develop tuberculosis (TB), though many may become latently infected. More precise measurement of the human immune response to M. tuberculosisinfection may help us understand this difference and potentially identify those subjects most at risk of developing active disease. Gamma interferon (IFN-?) production has been widely used as a proxy marker to study infection and to examine the human immune response to specific M. tuberculosisantigens. It has been suggested that genetically distinct M. tuberculosisstrains may invoke different immune responses, although how these differences influence the immune responses and clinical outcome in human tuberculosis is still poorly understood. We therefore evaluated the antigen-specific IFN-? production responses in peripheral blood mononuclear cells from two cohorts of subjects recruited in Antananarivo, Madagascar, from 2004 to 2006 and examined the influence of the infecting M. tuberculosisstrains on this response. The cohorts were sputum-positive index cases and their household contacts. Clinical strains isolated from the TB patients were typed by spoligotyping. Comparison of the IFN-? responses with the spoligotype of the infecting clinical strains showed that “modern” M. tuberculosisstrains, like Beijing and Central Asian (CAS) strains, tended to induce lower IFN-? responses than “ancient” strains, like East African-Indian (EAI) strains, in index cases and their household contacts. These results suggest that new strains may have evolved to induce a host response different from that of ancient strains. These findings could have important implications in the development of therapeutic and diagnostic strategies.

Human infection with Mycobacterium tuberculosiscan 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.

Although many studies have compared in vitroTB diagnostic tests with the venerable tuberculin skin test (TST), there is little understanding of the quantitative relationship between critical measures of antimycobacterial immunity used to detect TB infection. We, therefore, decided to determine the degree of redundancy between quantitative read-outs of in vivoand in vitroassays of antimycobacterial immunity.

The changing face of tuberculosis, with epidemics fueled by HIV and urbanization in much of the world and a relative increase in the importance of latent tuberculosis as a source of cases in the more economically developed countries, has led to a demand for more robust, clinically applicable diagnostic tools. As a result, research aiming to identify biomarkers of Mycobacterium tuberculosisinfection and disease has flourished. This article discusses the most recent findings of that work.

ABSTRACTThe 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.

More than 80 years after the introduction of Bacillus Calmette–GuÉrin, the first tuberculosis vaccine, new vaccines for tuberculosis are finally in clinical trials. The selection of antigens on which new subunit vaccines are based represent the first fulfilment of the promise of proteomics and �genomics, and the delivery systems for these antigens are likewise the first fruits of the improved understanding of how the host immune system recognizes pathogens. However, clinical trials are still at Phase I and there remain formidable obstacles to the registration of the first new TB vaccines. Here the authors review the vaccines in clinical trials and discuss the different approaches they take to stimulating immunity to Mycobacterium tuberculosisinfection, focusing on recombinant subunit vaccines. The challenges that confront these approaches and how they are being addressed are then discussed.

It is well known that the majority of healthy individuals exposed to Mycobacterium tuberculosis do not become clinically ill. We have previously shown that in recently exposed healthy contacts of tuberculosis (TB) patients, a strong immune response to the M. tuberculosis 6-kDa early secreted antigenic target (ESAT-6) virulence factor correlated with a higher risk of subsequent disease, although the mechanism was unclear at that time. Inspired by recent reports that elevated expression of interleukin-4 (IL-4) in health care workers exposed to M. tuberculosis also correlated with a higher risk of their subsequently developing disease, we examined expression of IL-4, its competitive antagonist IL-4δ2, and gamma interferon (IFN-γ) in healthy household contacts of TB patients from Ethiopia. We then compared cytokine expression to their recognition of ESAT-6 (which is largely restricted to members of the tuberculosis complex and which serves as a reliable marker of infection) or to Ag85A (an antigen that is conserved among the mycobacteria and serves as a nonspecific control). Our study shows that in these recently exposed individuals, there is a correlation between a strong response to ESAT-6 and elevated expression of IL-4. Further, elevated expression of IL-4 is associated with lower expression of its antagonistic splice variant IL-4δ2 and with the Th1 cytokine IFN-γ, suggesting that in these at-risk individuals, immunity is skewed away from a protective Th1 response, even before the development of clinical symptoms.

ABSTRACTMycobacterium tuberculosisis estimated to infect 80 to 100 million people annually, the majority of whom do not develop clinical tuberculosis (TB) but instead maintain the infection in a latent state. These individuals generally become positive in response to a tuberculin skin test and may develop clinical TB at a later date, particularly if their immune systems are compromised. Latently infected individuals are interesting for two reasons. First, they are an important reservoir of M. tuberculosis, which needs to be considered for TB control. Second, if detected prior to recrudescence of the disease, they represent a human population that is making a protective immune response to M. tuberculosis, which is very important for defining correlates of protective immunity. In this study, we show that while responsiveness to early secretory antigenic target 6 is a good marker for M. tuberculosisinfection, a strong response to the 16-kDa Rv2031c antigen (HspX or a-crystallin) is largely restricted to latently infected individuals, offering the possibility of differential immunodiagnosis of, or therapeutic vaccination against, TB.

SUMMARYThree-quarters of a century after the introduction of Mycobacterium bovisBCG, the first tuberculosis vaccine, new vaccines for tuberculosis are finally entering clinical trials. This breakthrough is based not only on advances in proteomics and genomics which have made the construction of new vaccines possible, but also on a greatly expanded knowledge of the immunology of tuberculosis. Here we review our current understanding of how Mycobacterium tuberculosissubverts or survives the host's immune response to cause disease and why the current vaccination strategy, which relies on BCG, is only partially successful in countering the pathogen. This provides a background for describing the new generation of vaccines designed to supplement or replace the current vaccine and the different approaches they take to stimulate immunity against M. tuberculosis.

ABSTRACTImproved diagnostic reagents are needed for the detection of Mycobacterium tuberculosisinfections, and the development of a serodiagnostic test would complement presently available diagnostic methods. The aim of the present study was to identify novel serological targets for use for the future serodiagnosis of tuberculosis (TB). We cloned and expressed 35 M. tuberculosis proteins as recombinant proteins in Escherichia coliand analyzed their serodiagnostic potentials. By a two-step selection process, four superior seroantigens, TB9.7, TB15.3, TB16.3, and TB51, were identified, none of which has been described before. The four novel antigens were tested with panels of sera from smear-positive and smear-negative TB patients from areas both where TB is endemic and where TB is not endemic, with recognition frequencies ranging from 31 to 93% and with a specificity of at least 97%. The single most potent antigen was TB16.3, which had a sensitivity of 48 to 55% with samples from Danish resident TB patients and a sensitivity of 88 to 98% with samples from African TB patients. Importantly, the TB16.3 and the TB9.7 antigens were recognized by more than 85% of the samples from TB patients coinfected with human immunodeficiency virus, a patient group for which it is in general difficult to detect M. tuberculosis-specific antibodies.

Immunity against Mycobacterium tuberculosis depends largely on activation of cell-mediated responses, and gamma interferon has been shown to play a crucial role in this process in both humans and animal models. Since the lung is normally the organ in which infection is initiated and is the major site of pathology, immune responses in the lung play a significant role in restricting initial infection with M. tuberculosis. The aim of the present study was to stimulate efficient immunity in the lung by targeting the gut mucosa. Detoxified monophosphoryl lipid A (MPL) has been shown to be a relatively nontoxic adjuvant which efficiently promotes the induction of type 1 responses when it is given by the traditional subcutaneous route. We have therefore compared subcutaneous immunization of mice to oral immunization by using a model subunit vaccine carrying two immunodominant proteins from M. tuberculosis, in combination with MPL-based adjuvants. While less effective when used to prime a response, a heterologous priming and boosting vaccination strategy employing oral boosting induced significant systemic type 1 responses which equaled and surpassed those attained by subcutaneous immunization protocols. Moreover, the increased immune responses observed correlated with the induction of substantial protection against subsequent aerosol infection with virulent M. tuberculosis at levels comparable to, or better than, those obtained by multiple subcutaneous vaccinations. These results demonstrate that booster vaccinations via mucosal surfaces, by combining efficient subunit vaccines with the potent adjuvant MPL, may be an effective method of addressing some of the shortcomings of current vaccination strategies.

If the end of the 20th century saw the flowering of genomics, the beginning of the 21st century is witnessing an equally rapid blossoming of proteomics. These twin technologies have had a dramatic influence on the study of tuberculosis (TB), and nowhere more so than in the development of new TB vaccines. Only a few years ago, it was generally accepted that clinical trials of new TB vaccines would not take place for at least a decade. However, the first trials are now scheduled to start within months. Much TB vaccine research has thus shifted from developing new vaccines, to selecting the best vaccines for human use from the increasing number of effective new candidates becoming available. This selection is being eased by the improved animal models that have been developed over the past few years and by our increasing understanding of immunity to TB.

The last year in tuberculosis vaccine research has witnessed the initial flowering of the benefits promised by the tuberculosis genome sequencing product. Although the real benefits in terms of clinical treatments are yet to be realized, genomics is making its presence felt in the rapid identification and expression of proteins with vaccine potential from Mycobacterium tuberculosis,the definition of species-specific antigens for diagnostic use, and the construction of a variety of novel living vectors for vaccination. At the same time, the recent increase in work on animal models with more direct applicability to the situations likely to be encountered in human vaccine trials are providing the basic underpinnings needed for the assessment of these new vaccines.

PROBLEM:The expression of the pregnancy‐specific glycoprotein (PSG) genes in the uterine endometrium of women experiencing recurrent first‐trimester abortions, and potential correlations to cytokine expression were examined.

Leishmania major, which causes cutaneous leishmaniasis in humans, can also infect mice, in which can cause either a local cutaneous lesion or a fatal disseminated infection. We have previously shown that BALB/c mice injected with antigen-pulsed macrophages derived from bone marrow with granulocyte-macrophage colony-stimulating factor (GMMφ), but not other types of macrophages, were protected from an otherwise lethal infection with L. major. The protection induced by GMMφ was shown to be antigen specific and correlated with the induction of a Th1-like response characterized by production of high levels of IFN-γ, delayed-type hypersensitivity reactivity and long-lived resistance to reinfection. In this report, we show that the protection induced in this disease model correlates with the sustained production of IL-12 synthesis by GMMφ in vitro and in vivo. Moreover, GMMφ deficient in the production of IL-12 were unable to induce protection in this model. Our data, therefore, suggest that a defect in macrophage activation or differentiation may play a significant role in the inability of BALB/c mice to respond effectively to L. major, and this mechanism may also be important in determining resistance to other intracellular parasites.

ABSTRACTWe examined the immune responses of patients with active pulmonary tuberculosis (TB) and their healthy household contacts to short-term culture filtrate (ST-CF) of Mycobacterium tuberculosisor molecular mass fractions derived from it. Our goal was to identify fractions strongly recognized by donors and differences among the donor groups of possible relevance for vaccine development. The study population consisted of 65 human immunodeficiency virus-negative donors from the Hossana Regional Hospital, Hossana, Ethiopia. Peripheral blood leukocytes from the donors were stimulated with different antigens and immune responses were determined. Household contacts produced significantly higher levels of gamma interferon (IFN-γ) than the TB patients in response to antigens present in ST-CF and the 10 narrow-molecular-mass fractions. A similar difference in leukocyte proliferative responses to the antigens between the two groups was also found. In general, while all fractions stimulated immune responses, the highest activity was seen with the low-molecular-mass fractions, which include well-defined TB antigens such as ESAT-6. Leukocytes from contacts of TB patients with severe disease produced higher levels of antigen-specific IFN-γ than those from contacts of patients with minimal disease. Both groups of contacts exhibited higher cell-mediated responses than the patients themselves. The enhanced immune response of healthy contacts, especially those of patients with severe disease, to secreted mycobacterial antigens is suggestive of an early stage of infection by M. tuberculosis, which could in time result in overt disease or containment of the infection. This possibility is currently being investigated by follow-up studies of the household contacts.

ABSTRACTChronic granulomatous disease (CGD) is a genetic disorder of NADPH oxidase in which phagocytes are defective in generating reactive oxidants. CGD patients suffer from recurrent infections and exuberant and persistent tissue granuloma formation. We hypothesized that abnormal granulomata in CGD may result from aberrant T-cell-mediated cytokine responses. To assess Th-1-type cytokine responses and granulomata, we challenged p47phox−/−and wild-type mice with avirulent (SmD) or virulent (SmT) variants ofMycobacterium avium2-151. To assess Th-2-type cytokine responses and granulomata, we used Schistosoma mansonieggs (SME). Mononuclear cells were harvested, and cytokine responses were determined by enzyme-linked immunosorbent assay or reverse transcriptase PCR. Following SmD or SmT challenge, splenocytes from p47phox−/−and wild-type mice generated similar polar Th-1 responses (increased levels of gamma interferon and basal levels of interleukin 4 [IL-4] and IL-5). By 8 weeks after SmT challenge, exuberant splenic granulomata developed in p47phox−/−and wild-type mice. After SME challenge, thoracic lymph node mononuclear cells from p47phox−/−and wild-type mice generated similar mixed Th-1 and Th-2 cytokine responses to SME antigen and concanavalin A. Peak lung granuloma sizes and rates of regression were similar in p47phox−/−and wild-type mice. These results suggest that exuberant granulomatous inflammation in CGD is probably not the result of skewing of T-cell responses toward the Th-1 or Th-2 pole. Appropriate regression of established tissue granulomata in p47phox−/−mice challenged with SME suggests that abnormal granuloma formation in CGD is stimulus dependent and is not an invariant feature of the disease.

Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a chronic myelogenous leukemia-like syndrome and mount impaired responses to certain viral and bacterial infections. To gain a mechanistic understanding of the contributions of ICSBP to humoral and cellular immunity, we characterized the responses of control and ICSBP−/− mice to infection with influenza A (flu) and Leishmania major (L. major). Mice of both genotypes survived infections with flu, but differed markedly in the isotype distribution of antiflu antibodies. In sera of normal mice, immunoglobulin (Ig)G2a antibodies were dominant over IgG1 antibodies, a pattern indicative of a T helper cell type 1 (Th1)-driven response. In sera of ICSBP−/− mice, however, IgG1 antibodies dominated over IgG2a antibodies, a pattern indicative of a Th2-driven response. The dominance of IgG1 and IgE over IgG2a was detected in the sera of uninfected mice as well. A seeming Th2 bias of ICSBP-deficient mice was also uncovered in their inability to control infection with L. major, where resistance is known to be dependent on IL-12 and IFN-γ as components of a Th1 response. Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-γ and macrophages of producing nitric oxide. Compromised Th1 differentiation in ICSBP−/− mice could not be attributed to hyporesponsiveness of CD4+ T cells to interleukin (IL)-12; however, the ability of uninfected and infected ICSBP-deficient mice to produce IL-12 was markedly impaired. This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.

ABSTRACTThe antitumor drug paclitaxel (Taxol) has been demonstrated to be a lipopolysaccharide mimetic in murine macrophages. In this study, the capacity of paclitaxel to activate macrophages to become microbicidal for Leishmania majorwas examined. Paclitaxel and gamma interferon synergized to kill intracellular L. majorinLpsn, but not Lpsd, macrophages by a nitric oxide (NO·)-dependent mechanism.

ABSTRACTDiagnosis of latent Mycobacterium tuberculosisinfection is considered essential for tuberculosis control but is hampered by the lack of specific reagents. We report that strong recognition of tuberculosis complex-specific antigen ESAT-6 by healthy household contacts of tuberculosis patients correlates with the subsequent development of active tuberculosis during a 2-year follow-up period.

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