Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?

In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB.     

Is Scale-Up Worth It? Challenges in Economic Analysis of Diagnostic Tests for Tuberculosis

David Dowdy and colleagues discuss the complexities of costing new TB diagnostic tests, including GeneXpert, and argue that flexible analytic tools are needed for decision-makers to adapt large-sample cost-effectiveness data to local conditions.     

Implementing the Xpert? MTB/RIF Diagnostic Test for Tuberculosis and Rifampicin Resistance: Outcomes and Lessons Learned in 18 Countries

Background

The Xpert^® MTB/RIF (Xpert) is an automated molecular test for simultaneous detection of tuberculosis (TB) and rifampicin resistance, recommended by the World Health Organization as the preferred diagnostic method for individuals presumed to have multi-drug resistant TB (MDR-TB) or HIV-associated TB. We describe the performance of Xpert and key lessons learned during two years of implementation under routine conditions in 33 projects located in 18 countries supported by Médecins Sans Frontières across varied geographic, epidemiological and clinical settings.

Methods

Xpert was used following three strategies: the first being as the initial test, with microscopy in parallel, for all presumptive TB cases; the second being only for patients at risk of MDR-TB, or with HIV- associated TB, or presumptive paediatric TB; and the third being as the initial test for these high-risk patients plus as an add-on test to microscopy in others. Routine laboratory data were collected, using laboratory registers. Qualitative data such as logistic aspects, human resources, and tool acceptance were collected using a questionnaire.

Findings

In total, 52,863 samples underwent Xpert testing from April 2011 to December 2012. The average MTB detection rate was 18.5%, 22.3%, and 11.6% for the three different strategies respectively. Analysis of the results on samples tested in parallel showed that using Xpert as add-on test to microscopy would have increased laboratory TB confirmation by 49.7%, versus 42.3% for Xpert replacing microscopy. The main limitation of the test was the high rate of inconclusive results, which correlated with factors such as defective modules, cartridge version (G3 vs. G4) and staff experience. Operational and logistical hurdles included infrastructure renovation, basic computer training, regular instrument troubleshooting and maintenance, all of which required substantial and continuous support.

Conclusion

The implementation of Xpert was feasible and significantly increased TB detection compared to microscopy, despite the high rate of inconclusive results. Xpert implementation was accompanied by considerable operational and logistical challenges. To further decentralize diagnosis, simpler, low-cost TB technologies well-suited to low-resource settings are still urgently needed.     

How Much Ecology Do We Need to Know to Restore Mediterranean Ecosystems?

Despite important advances in ecological knowledge of Mediterranean‐type ecosystems, advances in restoration ecology have not seen a parallel increase in these systems. Although some concepts such as positive plant–plant interaction (facilitation) have received attention in the restoration ecology community, others such as phenotypic plasticity have not. Some concepts (e.g., environmental heterogeneity) are mature enough for a wide use in restoration, whereas available knowledge on others (e.g., facilitation, plasticity) is less conclusive. However, the scientific knowledge is in general enough to significantly improve the guidelines for restoration of Mediterranean ecosystems. Our review suggests that (1) the extent of facilitation in dry ecosystems is partially understood, with supporting, but somewhat contradictory empirical evidence for its potential use in restoration; (2) the influence of habitat heterogeneity on plant performance and plasticity is only beginning to be understood, with a strong bias toward patterns of structural heterogeneity and negligible information on functional heterogeneity; and (3) sound evaluations of phenotypic plasticity might be useful to increase the success of restoration practices in patchy Mediterranean environments. Future global change scenarios involving temperature rise, reduced precipitation, increased frequency of extreme climatic events, and important land use changes and fragmentation must be particularly considered when restoring Mediterranean ecosystems. Further research on how to incorporate results on facilitation, environmental heterogeneity, and plasticity within a global change framework is clearly needed.     

Do We Produce Enough Fruits and Vegetables to Meet Global Health Need?

Background

Low fruit and vegetable (FV) intake is a leading risk factor for chronic disease globally, but much of the world’s population does not consume the recommended servings of FV daily. It remains unknown whether global supply of FV is sufficient to meet current and growing population needs. We sought to determine whether supply of FV is sufficient to meet current and growing population needs, globally and in individual countries.

Methods and Findings

We used global data on agricultural production and population size to compare supply of FV in 2009 with population need, globally and in individual countries. We found that the global supply of FV falls, on average, 22% short of population need according to nutrition recommendations (supply:need ratio: 0.78 [Range: 0.05–2.01]). This ratio varies widely by country income level, with a median supply:need ratio of 0.42 and 1.02 in low-income and high-income countries, respectively. A sensitivity analysis accounting for need-side food wastage showed similar insufficiency, to a slightly greater extent (global supply:need ratio: 0.66, varying from 0.37 [low-income countries] to 0.77 [high-income countries]). Using agricultural production and population projections, we also estimated supply and need for FV for 2025 and 2050. Assuming medium fertility and projected growth in agricultural production, the global supply:need ratio for FV increases slightly to 0.81 by 2025 and to 0.88 by 2050, with similar patterns seen across country income levels. In a sensitivity analysis assuming no change from current levels of FV production, the global supply:need ratio for FV decreases to 0.66 by 2025 and to 0.57 by 2050.

Conclusion

The global nutrition and agricultural communities need to find innovative ways to increase FV production and consumption to meet population health needs, particularly in low-income countries.     

Direct Observation (DO) for Drug-Resistant Tuberculosis: Do We Really DO?

Introduction

Directly-observed therapy (DOT) is recommended for drug-resistant tuberculosis (DR-TB) patients during their entire treatment duration. However, there is limited published evidence on implementation of direct observation (DO) in the field. This study aims to detail whether DO was followed with DR-TB patients in a Médecins Sans Frontières (MSF) tuberculosis program in Mumbai, India.

Methods

This was a cross-sectional, mixed-methods study. Existing qualitative data from a purposively-selected subset of 12 patients, 5 DOT-providers and 5 family members, were assessed in order to determine how DO was implemented. A questionnaire-based survey of DR-TB patients, their DOT-providers and MSF staff was completed between June and August 2014. Patients were defined as”following Strict DO” and “following DO” if a DOT-provider had seen the patient swallow his/her medications “every day” or “most of the days” respectively. If DO was not followed, reasons were also recorded. The qualitative data were analysed for theme and content and used to supplement the questionnaire-based data.

Results

A total of 70 DR-TB patients, 65 DOT-providers and 21 MSF health staff were included. Fifty-five per cent of the patients were HIV-co-infected and 41% had multidrug-resistant-TB plus additional resistance to a fluoroquinolone. Among all patients, only 14% (10/70) and 20% (14/70) self-reported “following Strict DO” and “following DO” respectively. Among DOT-providers, 46% (30/65) reported that their patients “followed DO”. MSF health staff reported none of the patients “followed DO”. Reasons for not implementing DO included the unavailability of DOT-provider, time spent, stigma and treatment adverse events. The qualitative data also revealed that “Strict DO” was rarely followed and noted the same reasons for lack of implementation.

Conclusion

This mixed-methods study has found that a majority of patients with DR-TB in Mumbai did not follow DO, and this was reported by patients and care-providers. These data likely reflect the reality of DO implementation in many high-burden settings, since this relatively small cohort was supported and closely monitored by a skilled team with access to multiple resources. The findings raise important concerns about the necessity of DO as a “pillar” of DR-TB treatment which need further validation in other settings. They also suggest that patient-centred adherence strategies might be better approaches for supporting patients on treatment.     

Tools and Strategies for Malaria Control and Elimination: What Do We Need to Achieve a Grand Convergence in Malaria?

Progress made in malaria control during the past decade has prompted increasing global dialogue on malaria elimination and eradication. The product development pipeline for malaria has never been stronger, with promising new tools to detect, treat, and prevent malaria, including innovative diagnostics, medicines, vaccines, vector control products, and improved mechanisms for surveillance and response. There are at least 25 projects in the global malaria vaccine pipeline, as well as 47 medicines and 13 vector control products. In addition, there are several next-generation diagnostic tools and reference methods currently in development, with many expected to be introduced in the next decade. The development and adoption of these tools, bolstered by strategies that ensure rapid uptake in target populations, intensified mechanisms for information management, surveillance, and response, and continued financial and political commitment are all essential to achieving global eradication.     

Which New Health Technologies Do We Need to Achieve an End to HIV/AIDS?

In the last 15 years, antiretroviral therapy (ART) has been the most globally impactful life-saving development of medical research. Antiretrovirals (ARVs) are used with great success for both the treatment and prevention of HIV infection. Despite these remarkable advances, this epidemic grows relentlessly worldwide. Over 2.1 million new infections occur each year, two-thirds in women and 240,000 in children. The widespread elimination of HIV will require the development of new, more potent prevention tools. Such efforts are imperative on a global scale. However, it must also be recognised that true containment of the epidemic requires the development and widespread implementation of a scientific advancement that has eluded us to date—a highly effective vaccine. Striving for such medical advances is what is required to achieve the end of AIDS.In the last 15 years, antiretroviral therapy (ART) has been the most globally impactful life-saving development of medical research. Antiretrovirals (ARVs) are used with great success for both the treatment and prevention of HIV infection. In the United States, the widespread implementation of combination ARVs led to the virtual eradication of mother-to-child transmission of HIV from 1,650 cases in 1991 to 110 cases in 2011, and a turnaround in AIDS deaths from an almost 100% five-year mortality rate to a five-year survival rate of 91% in HIV-infected adults [1]. Currently, the estimated average lifespan of an HIV-infected adult in the developed world is well over 40 years post-diagnosis. Survival rates in the developing world, although lower, are improving: in sub-Saharan Africa, AIDS deaths fell by 39% between 2005 and 2013, and the biggest decline, 51%, was seen in South Africa [2].Furthermore, the association between ART, viremia, and transmission has led to the concept of “test and treat,” with the hope of reducing community viral load by testing early and initiating treatment as soon as a diagnosis of HIV is made [3]. Indeed, selected regions of the world have begun to actualize the public health value of ARVs, from gains in life expectancy to impact on onward transmission, with a potential 1% decline in new infections for every 10% increase in treatment coverage [2]. In September 2015, WHO released new guidelines removing all limitations on eligibility for ART among people living with HIV and recommending pre-exposure prophylaxis (PrEP) to population groups at significant HIV risk, paving the way for a global onslaught on HIV [4].Despite these remarkable advances, this epidemic grows relentlessly worldwide. Over 2.1 million new infections occur each year, two-thirds in women and 240,000 in children [2]. In heavily affected countries, HIV infection rates have only stabilized at best: the annualized acquisition rates in persons in their first decade of sexual activity average 3%–5% yearly in southern Africa [5–7]. These figures are hardly compatible with the international health community’s stated goal of an “AIDS-free generation” [8,9]. In highly resourced settings, microepidemics of HIV still occur, particularly among gays, bisexuals, and men who have sex with men (MSM) [10]. HIV epidemics are expanding in two geographic regions in 2015—the Middle East/North Africa and Eastern Europe/Central Asia—largely due to challenges in implementing evidence-based HIV policies and programmes [2]. Even for the past decade in the US, almost 50,000 new cases recorded annually, two-thirds among MSM, has been a stable figure for years and shows no evidence of declining [1].While treatment scale-up, medical male circumcision [11], and the implementation of strategies to prevent mother-to-child transmission [12] have received global traction, systemic or topical ARV-based biomedical advances to prevent sexual acquisition of HIV have, as yet, made limited impressions on a population basis, despite their reported efficacy. Factors such as their adherence requirements, cost, potential for drug resistance, and long-term feasibility have restricted the appetite for implementation, even though these approaches may reduce HIV incidence in select populations.Already, several trials have shown that daily oral administration of the ARV tenofovir disoproxil fumarate (TDF), taken singly or in combination with emtricitabine, as PrEP by HIV-uninfected individuals, reduces HIV acquisition among serodiscordant couples (where one partner is HIV-positive and the other is HIV-negative) [13], MSM [14], at-risk men and women [15], and people who inject drugs [16,17] by between 44% and 75%. Long-acting injectable antiretroviral agents such as rilpivirine and cabotegravir, administered every two and three months, respectively, are also being developed for PrEP. All of these PrEP approaches are dependent on repeated HIV testing and adherence to drug regimens, which may challenge effectiveness in some populations and contexts.The widespread elimination of HIV will require the development of new, more potent prevention tools. Because HIV acquisition occurs subclinically, the elimination of HIV on a population basis will require a highly effective vaccine. Alternatively, if vaccine development is delayed, supplementary strategies may include long-acting pre-exposure antiretroviral cocktails and/or the administration of neutralizing antibodies through long-lasting parenteral preparations or the development of a “genetic immunization” delivery system, as well as scaling up delivery of highly effective regimens to eliminate mother-to-child HIV transmission (Fig 1).Open in a separate windowFig 1Medical interventions required to end the epidemic of HIV.Image credit: Glenda Gray.     

Replication Origins: Why Do We Need So Many?

During the G1 phase of the cell cycle, replication origins are prepared to fire, a process that is referred to as origin licensing. It was often pondered what a cell’s fate would be if not all of its replication origins were licensed and subsequently activated during S phase. One obvious prediction was that S phase would simply be prolonged. As it turns out, however, the consequences are much more complex. A short G1 phase enforced by premature entry into S phase, or other events that negatively affect origin licensing, will ultimately compromise the cell’s ability to complete DNA replication before entering mitosis. As a result, the cell becomes genomically unstable when it attempts to repair unreplicated DNA during anaphase. Thus, the density of active replication origins in the chromosomes of eukaryotic cells determines S phase dynamics and chromosome stability during mitosis.     

Do We Need Surveillance Urethro-Cystoscopy in Patients with Neurogenic Lower Urinary Tract Dysfunction?

Purpose

To examine the value of surveillance urethro-cystoscopy in patients with neurogenic lower urinary tract dysfunction (NLUTD) in regard to the conflicting literature as it is generally agreed that patients with NLUTD are at increased risk for bladder cancer.

Materials and Methods

In a cross-sectional study, a consecutive series of 129 patients (50 females, 79 males, mean age 51, range 18–88) suffering from NLUTD for at least 5 years was prospectively investigated using urethro-cystoscopy and bladder washing cytology at a single university spinal cord injury (SCI) center.

Results

Due to suspicious urethro-cystoscopy and/or bladder washing cytology findings, 13 (10%) of 129 patients underwent transurethral resection of the bladder lesion and/or random bladder biopsies. Overall, 9 relevant histological findings were found in 5% (7/129) of our patients: bladder melanosis (n = 1), nephrogenic adenoma (n = 3), keratinizing squamous metaplasia (n = 1), intestinal metaplasia (n = 3), and muscle-invasive adenocarcinoma of the bladder (n = 1).

Conclusions

Using surveillance urethro-cystoscopy, we found relevant histological findings in 5% of our patients suffering from NLUTD for at least 5 years. Thus, surveillance urethro-cystoscopy might be warranted, although the ideal starting point and frequency remain to be determined in further prospective studies.     

Characterizing Protease Specificity: How Many Substrates Do We Need?

Calculation of cleavage entropies allows to quantify, map and compare protease substrate specificity by an information entropy based approach. The metric intrinsically depends on the number of experimentally determined substrates (data points). Thus a statistical analysis of its numerical stability is crucial to estimate the systematic error made by estimating specificity based on a limited number of substrates. In this contribution, we show the mathematical basis for estimating the uncertainty in cleavage entropies. Sets of cleavage entropies are calculated using experimental cleavage data and modeled extreme cases. By analyzing the underlying mathematics and applying statistical tools, a linear dependence of the metric in respect to 1/n was found. This allows us to extrapolate the values to an infinite number of samples and to estimate the errors. Analyzing the errors, a minimum number of 30 substrates was found to be necessary to characterize substrate specificity, in terms of amino acid variability, for a protease (S4-S4’) with an uncertainty of 5 percent. Therefore, we encourage experimental researchers in the protease field to record specificity profiles of novel proteases aiming to identify at least 30 peptide substrates of maximum sequence diversity. We expect a full characterization of protease specificity helpful to rationalize biological functions of proteases and to assist rational drug design.     

Why Do We Expect Carotenoids to be Antioxidants in vivo?

The antioxidant properties of β-carotene, in addition to its proposed immunomodulatory effects, have often been cited as the factors underlying its role in preventing disease initiation and propagation, yet the strongest evidence for diet and cancer prevention is based on fruit and vegetable intake and not β-carotene or other dietary carotenoids, per se. In the light of the outcome of the ATBC trial, the Physicians Health Study and the premature termination of the CARET study, this review addresses the issue of the antioxidant properties of the carotenoids and poses the questions: do dietary carotenes and xanthophylls have a clear role in disease prevention and are their antioxidant properties relevant to this role? What. do we know about their mechanisms of action in vitro as free radical scavengers?