Immune protection against tuberculosis--when is immunotherapy preferable to vaccination?

In view of the limited protection against tuberculosis, especially the infectious forms of pulmonary tuberculosis, afforded by Bacille Calmette-Guérin (BCG) vaccination, attempts are being made to develop more effective alternatives. Many of these attempts are based on the classical strategy of selecting 'protective' epitopes of Mycobacterium tuberculosis to induce immune responses in the vaccinated host. Such strategies, which in the past have been applied very effectively for the prevention of many acute infectious diseases, may not be relevant for a chronic disease in which both pathogen and host have co-evolved so that the majority of infected individuals remain asymptomatic, albeit latently infected, and in which inappropriate, dysregulated, patterns of immune reactivity predispose to, and maintain, the long-term pathological processes in a minority of symptomatic diseased individuals. While immune responses against the causative pathogen are of doubtless importance in the mediation of protection in the asymptomatic majority, we postulate that it is equally, or more, significant for public health to induce the required protective pattern of immune reactivity by immunotherapy in the diseased minority.

Melanoma, Darwinian medicine and the inner world.

INTRODUCTION: A diverse range of human diseases, including allergy, asthma, autoimmune disease, cancer and chronic neurologic diseases, notably multiple sclerosis and endogenous depression, is becoming more prevalent in industrialized countries. It has been postulated that environmental factors associated with improved standards of hygiene play a leading role in this process since the immune system seems to need extrinsic challenges for its proper maturation. THE INNER WORLD: An added dimension has now emerged--the impact on disease of the inner world, principally the numerous endogenous retroviruses (HERVs) within the human genome. Taking melanoma as an example, we propose a framework for understanding how a complex infectious and immunological background can induce or inhibit expression of a HERV-related disease process. The central role of a failure to induce or to maintain certain populations of self-specific CD8(+) T-cells mediating immune surveillance, the expression of HERV-encoded peptides on affected cells and pathological mechanisms directly attributable to HERV proteins are discussed. CONCLUSIONS: The presented concepts explain events preceding the clinical manifestation of diseases by several years and provide a rationale for the use of currently available vaccines to protect against certain HERV-induced diseases, especially melanoma. Criteria for establishing the causal role of HERVs in a given disease are proposed.

Chronic inflammation as a manifestation of defects in immunoregulatory networks: implications for novel therapies based on microbial products.

Based on a unifying theory presented here, it is predicted that the immune defects resulting in chronic inflammation rather than effective immune responses could be rectified by the therapeutic use of agents prepared from micro-organisms. With appropriate molecular patterns, these should be able to induce protective immunoregulatory networks or to reprogramme defective ones. In contrast to acute inflammation, chronic inflammation appears to have no beneficial role, but is a state of sustained immune reactivity in the presence or progression of a disease process. This results in an escalating cycle of tissue damage followed by unproductive tissue repair, breaks in self-tolerance, malignant transformation or deleterious changes in tissue morphology and function. Such inappropriate immune reactivity is an underlying characteristic, either in initiation or maintenance, of a diverse range of disease states including chronic infection, autoimmunity, allergy, cancer, vascular disease and metabolic alterations. Evidence is presented that the inappropriate immune reactivity is due, at least to some extent, to failures in the establishment of immunoregulatory networks as a result of hygiene-related factors. Such networks are the result of activation of antigen-presenting cells, principally dendritic cells, by molecular patterns of micro-organisms encountered sequentially during life and establishing the 'biography' of the immune system.

Does yellow fever 17D vaccine protect against melanoma?

BCG vaccine, vaccinia vaccine and certain pathogens that were shown in previous studies to protect against melanoma have antigenic determinants homologous in their amino acids sequence with the melanoma antigen HERV-K-MEL, encoded by a human endogenous retrovirus K (HERV-K), which is expressed in about 95% of malignant melanocytes. Yellow fever vaccine (YFV) likewise contains an antigenic determinant with a close homology to HERV-K-MEL and might therefore also confer protection against melanoma. To investigate this possibility we carried out a cohort study (28,306 subjects) and a nested case-control study (37 melamona cases and 151 tumors not expressing HERV-K-MEL) in Veneto region (North-Eastern Italy). The standardized incidence ratio was 1.33 (95% confidence interval, 0.84-2.11), 1.59 (0.97-2.59) and 0.59 (0.19-1.84), while the age- gender-adjusted odds ratios were 1.00, 0.96 (0.43-2.14) and 0.26 (0.07-0.96), at 0-4, 5-9, and > or =10 years elapsed from YFV administration, respectively. The risk of melanoma may therefore be lowered 10 years after vaccination with yellow fever vaccine.

The use of mycobacterial adjuvant-based agents for immunotherapy of cancer.

A heat-killed preparation of Mycobacterium vaccae (SRL172) has been shown, in recent studies, to be effective in the treatment of adenocarcinoma of the lung and renal cell cancer. It is postulated that the mechanisms of this form of immunotherapy is, at least in part, due to immune regulation, reflected in the selective enhancement of Th1 and down-regulation of Th2 T cell activity. These beneficial effects are attributed to the ability of adjuvants in the bacterial cell walls to modify and optimise the response to antigens shared by the bacteria and stressed host tissues, resulting in the destruction of cancer cells by programmed cell death or apoptosis. The M. vaccae-induced apoptosis appears to be most effective against carcinomas, perhaps especially those of glandular tissue, in contrast to pyrexia-induced necrosis which is most effective against tumours of mesodermal origin. In view of the great range of adjuvants, especially in the genus Mycobacterium and related genera, it may prove possible to develop a range of immunotherapeutic agents with useful activity against a wide range of cancers.

Successful immunotherapy with Mycobacterium vaccae in the treatment of adenocarcinoma of the lung.

Immunotherapy with a heat-killed suspension of Mycobacterium vaccae (SRL172), given with chemotherapy, in a phase III trial against non-small-cell-lung cancer showed no improvement in the primary endpoint of survival over chemotherapy alone in the initial published analysis. Compliance was poor, with on average only 53% of patients receiving more than 2 injections in the SRL172 arm of the study. Quality of life was, however, improved in those receiving SRL172. Secondary analyses based on compliance with therapy showed that immunotherapy led to significantly improved survival times of patients with adenocarcinoma but, by contrast, had no beneficial effect on survival times of patients with squamous cell carcinoma. Survival of adenocarcinoma patients receiving SRL172 was increased by a mean of 135 days (p=0.0009, Kaplan-Meier log rank test) and survival after 4 or 5 doses of SRL172 showed a difference of greater than 100 days (p<0.05, Mantel-Hänszel log rank test) in the group receiving SRL172 in addition to chemotherapy. Despite the problems inherent in a secondary analysis, these results encourage further research on the role of killed preparations of adjuvant-rich micro-organisms, including saprophytic mycobacteria such as M. vaccae, and members of related genera in the therapy of a range of cancers.

Elevated lung cancer risk shortly after smoking cessation: is it due to a reduction of endotoxin exposure?

Several reports indicate that the risk of lung cancer increases slightly for a short period of time after cessation of smoking while the risk of adverse cardiovascular events drops immediately. Recent studies on subjects occupationally exposed to organic dust-containing endotoxin have revealed lower than expected rates of lung cancer. There is experimental evidence that stimulation of the immune system by endotoxin has a protective effect against cancer. Tobacco smoke has been shown to contain high levels of endotoxin. We therefore postulate that cessation of smoking eliminates the protective effect of endotoxin. Any benefit conferred by endotoxin does not, however, justify smoking. As the inverse relationship between exposure to endotoxin and the risk of lung cancer is a strong one, endotoxin-like substances could form the basis of vaccination strategies.

Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients.

There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guerin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.

Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study.

A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a 'masking effect' by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.

The global emergency of tuberculosis: what is the cause?

The treatment of tuberculosis is cheap and highly effective, yet worldwide the disease remains a serious cause of illness and death; so serious as to have been declared a 'global emergency' in 1993. It is principally a disease of poverty, with 95% of cases and 98% of deaths occurring in developing countries. The incidence of tuberculosis is increasing worldwide, partly due to poverty and inequity and partly to the HIV/AIDS pandemic, which greatly increases the risk of infection proceeding to overt disease. Around 30% of AIDS-related deaths are due to tuberculosis. The emergence of multidrug resistant tuberculosis (MDRTB) is an increasing threat to tuberculosis control. Although treatable with alternative drugs, the cost is enormous and, accordingly, not undertaken in many poor nations. While the overall global incidence of MDRTB is low, it occurs in certain 'hotspots' including Russian prisons. Due to adverse socio-economic factors, London has not escaped the general rise in incidence and, without the introduction of active control strategies, there could be a serious epidemic as occurred in New York City ten years ago which required an enormous financial outlay for its control. In view of the global emergency of tuberculosis, the WHO 'Stop TB' campaign has called for the universal adoption of its directly observed therapy, short course (DOTS) strategy. Also, though the Massive Effort Against Diseases of Poverty, several international agencies are urging the establishment of effective control programmes worldwide. London should take the lead and set an example.

Environmental echoes.

Allergy, auto immunity and cancer are becoming more prevalent in the developed world. One explanation might be that the immune system required to protect us from such problems is being inadequately trained, perhaps due to our increased separation from the environment which has shaped our mutating genes since we emerged from the primaeval ooze. Those infections which were the essential primers of our immunity are being prevented and action is needed to refocus the immune response without exposing us to the diseases of the past. In this paper we assess our place in relation to the environment and consider ways in which the situation can be redressed. There are considerable similarities between the immune system and human consciousness. Both enter the world in considerable ignorance of the events awaiting them, yet with the genetic ability, endowed by millennia of selection and evolution, to experience the world, to interpret and act on the experiences and to retain memory of the experiences. In both systems, maternal influences and early environmental encounters have profound effects on determining the patterns of subsequent responses. Ideally the 'learned' responses will benefit or protect the individual but inappropriate responses may lead to self damage. As the environment has altered irrevocably, attention must be paid to regulating the balance of immunological responsiveness to that expected of the normal immunological learning process. This should be possible by novel vaccination strategies.

Mycobacterium bovis infection in human beings.

The causative agent of bovine tuberculosis, Mycobacterium bovis, is also responsible for some cases of tuberculosis in human beings. Although recognized for over a century, this form of human tuberculosis has been a source of considerable misunderstanding and controversy. Questions still remain concerning the relative virulence of M. tuberculosis and M. bovis in human beings, the risk of human disease after infection, the immunological consequences of infection that does not proceed to disease, the occurrence of human-to-human transmission of M. bovis and the health risk of diseased human beings to cattle. The advent of the HIV/AIDS pandemic raises new questions of the epidemiological impact of immunosuppression on the transmission of M. bovis to and between human beings. Although largely eradicated in the developed nations, bovine tuberculosis still occurs in many developing nations and epidemiological data on the impact of this on human health is scanty but, in the light of the increasing incidence of tuberculosis worldwide, it is urgently needed.

Does immunotherapy with heat-killed Mycobacterium vaccae offer hope for the treatment of multi-drug-resistant pulmonary tuberculosis?

The ability of immunotherapy with heat-killed Mycobacterium vaccae (NCTC 11659), as an addition to the available chemotherapy, to improve the outcome in patients with multi-drug-resistant tubercle bacilli (MDRTB) who had not been cured by chemotherapy alone was evaluated in tuberculosis centres in Estonia, Iran, Kuwait, New Zealand, Romania, Vietnam and the U.K. A total of 337 patients in the above countries received intradermal injections of M. vaccae in addition to chemotherapy. Patients were grouped according to the length of their histories of disease: less than or greater than 2 years duration. Initially, single doses of M. vaccae were given but subsequently up to 12 doses at 2-month intervals were given. Chemotherapy varied from isoniazid alone to drugs selected according to susceptibility tests. Most patients had failed to respond to repeated courses of chemotherapy and the majority, were expected to die from their disease. Results were assessed by sputum smear and culture and by clinical observations. Cured patients were followed for 18-24 months to exclude relapse. Eighteen of 22 (82%) patients with disease for less than 2 years were bacteriologically cured by one or two doses of M. vaccae. Among 315 chronic patients, 24 (7.6%) were cured after one dose, 37.9% after seven doses and 41.6% after 12 doses. Sixty-six chronic patients were lost to follow-up, or died, during the multi-dose regimens. Nine of 33 patients (27%) with advanced disease unaffected by several courses of chemotherapy and discharged on isoniazid alone in Vietnam were cured by 3-12 injections of M. vaccae. The data provide preliminary evidence that the addition of immunotherapy with M. vaccae to chemotherapy improves the rate of cure of MDRTB, most effectively in patients with short histories of disease, but multiple dosing can have beneficial effects in chronic patients in whom chemotherapy has failed. A randomized clinical trial of this immunotherapy in MDRTB patients is therefore required.

Historical declines in tuberculosis: nature, nurture and the biosocial model.

The large declines in the incidence of tuberculosis over time in the industrially developed nations have usually been attributed to natural selection or to socio-economic improvements. Both explanations are beset with problems, as there is little firm evidence for the occurrence of natural selection of resistance to tuberculosis to any significant extent, and doubts have been expressed as to whether the incidence of a disease can be directly related to measures of socio-economic change without consideration of the impact of the many specific public health measures that have been taken. In addition, analyses of the changing prevalence of tuberculosis must consider the impact of changing environmental and ecological factors that affect, for example, the immunising effect of exposure to Mycobacterium bovis and saprophytic mycobacteria. It is also necessary to determine whether the causative organism is undergoing evolutionary change, as recent reports suggest.

Multidrug-resistant tuberculosis--can the tide be turned?

Despite continued control efforts, tuberculosis remains a leading cause of illness and death worldwide, with more cases today than at any previous time in history. Not only is there a global increase in the disease itself, there is a worrying rise in the number of cases resistant to the two principal antituberculosis drugs, isoniazid and rifampicin--so called multidrug resistance.